Zeitschriftenartikel zum Thema „Upper Canada Committee“

IntroductionTheRe-Evaluating theInhibition ofStressErosions (REVISE) Trial aims to determine the impact of the proton pump inhibitor pantoprazole compared with placebo on clinically important upper gastrointestinal (GI) bleeding in the intensive care unit (ICU), 90-day mortality and other endpoints in critically ill adults. The objective of this report is to describe the rationale, methodology, ethics and management of REVISE.Methods and analysisREVISE is an international, randomised, concealed, stratified, blinded parallel-group individual patient trial being conducted in ICUs in Canada, Australia, Saudi Arabia, UK, US, Kuwait, Pakistan and Brazil. Patients≥18 years old expected to remain invasively mechanically ventilated beyond the calendar day after enrolment are being randomised to either 40 mg pantoprazole intravenously or an identical placebo daily while mechanically ventilated in the ICU. The primary efficacy outcome is clinically important upper GI bleeding within 90 days of randomisation. The primary safety outcome is 90-day all-cause mortality. Secondary outcomes include rates of ventilator-associated pneumonia,Clostridioides difficileinfection, new renal replacement therapy, ICU and hospital mortality, and patient-important GI bleeding. Tertiary outcomes are total red blood cells transfused, peak serum creatinine level in the ICU, and duration of mechanical ventilation, ICU and hospital stay. The sample size is 4800 patients; one interim analysis was conducted after 2400 patients had complete 90-day follow-up; the Data Monitoring Committee recommended continuing the trial.Ethics and disseminationAll participating centres receive research ethics approval before initiation by hospital, region or country, including, but not limited to – Australia: Northern Sydney Local Health District Human Research Ethics Committee and Mater Misericordiae Ltd Human Research Ethics Committee; Brazil: Comissão Nacional de Ética em Pesquisa; Canada: Hamilton Integrated Research Ethics Board; Kuwait: Ministry of Health Standing Committee for Coordination of Health and Medical Research; Pakistan: Maroof Institutional Review Board; Saudi Arabia: Ministry of National Guard Health Affairs Institutional Review Board: United Kingdom: Hampshire B Research Ethics Committee; United States: Institutional Review Board of the Nebraska Medical Centre. The results of this trial will inform clinical practice and guidelines worldwide.Trial registration numberNCT03374800.

In 1787, a group of American refugee settlers in the western portion of Quebec, which would become the colony of Upper Canada in 1791, collectively petitioned the Governor General, Lord Dorchester, for schools. They insisted, in fact, on a relatively comprehensive network of schools funded directly through the government purse. Dorchester responded by appointing William Smith, the former Chief Justice of New York State with whom he had formed a political friendship during the American War of Independence, to head a special committee to report on the state of education throughout the entire province. Several hundred copies of the report were printed and released in 1789. The report recommended a government-supported tripartite elementary, secondary, and university school system. The recommendations were not acted upon, but the report's ideas lingered in public discourse for years to come. In the writing of the origins of schooling in Upper Canada, this report has not received considerable attention. Moreover, the intentions and goals of these early settlers advocating for government-aided schooling are characteristically overlooked. In the dominant view, the building of Upper Canada's school system was motivated by the bureaucratization and institutionalization concerns of major school advocates and politicians in the mid-nineteenth century.

In situ U–Pb sensitive high-resolution ion microprobe (SHRIMP) analyses of monazite from upper amphibolite-facies paragneiss of the Committee Bay supracrustal belt, central Rae domain, Canada, reveal three age populations: ca. 2350, 1850, and 1780 Ma. The ca. 1850 Ma age also corresponds to growth of low Th/U zircon as indicated by U–Pb SHRIMP analyses of zircon separates from melanosome and leucosome. The contextual advantage of the in situ monazite analysis allows evaluation of the geochronological data in terms of the regional structural and metamorphic evolution. The region is dominated by a northeast-striking S2 (±S1) fabric, axial planar to tight, northwest-vergent F2 folds. Early garnet is enveloped by this biotite–sillimanite ± cordierite S2 fabric. GarnetI hosts ca. 1850 Ma monazite inclusions (with ca. 2350 Ma cores), placing a maximum age on garnetI growth and S2 development. D2 metamorphic conditions progressed through ~3.5 kbar (1 kbar = 100 MPa) and 600 °C to near-peak conditions of ~5 kbar and 675 °C. A minimum age for S2 is provided by unstrained ca. 1820 Ma monzogranite that locally, and regionally, truncates S2. Dominantly ca. 1780 Ma matrix monazite is interpreted to date post-S2 garnetII and cordierite, which record ~5 kbar and 675 °C. These data indicate that the Committee Bay region experienced penetrative D2 tectonometamorphism at ca. 1850–1820 Ma, with a subsequent static overprint. The absence of a ca. 1.85 Ga plutonic suite in the region suggests that low-pressure metamorphism was a response to thick-skinned crustal thickening initiated at ca. 1870 Ma. The new data highlight the importance of Paleoproterozoic reworking of the central Rae domain in the hinterland of the Trans-Hudson orogen.

Abstract. The extent of global change in carbon system parameters can only be evaluated by comparing present with past measurements. In the northern North Pacific, where aragonite saturation horizons are among the shallowest in the world, historical measurements of carbonate parameters vary from rare to nonexistent. However, during the summer of 1956 and winter of 1957, an extensive survey of the oceanography of the Northeast Pacific, under the auspices of the Canadian Committee on Oceanography, was conducted by the Fisheries Research Board of Canada. Approximately 2500 measurements of pH at depths from surface to 2000 m were taken throughout the Gulf of Alaska, in addition to measurements of nutrient and hydrographic properties. After conversion to the contemporary total pH scale, these data revealed significant seasonal and latitudinal differences in pH in the upper 200 m. Estimates of aragonite saturation indicate that undersaturated water was a common feature of the surface mixed layer north of 51° N latitude in the winter of 1957. The North Pacific Survey data were compared with the results of a summer 2007 survey of the west coast of North America where pH levels were ~0.1 pH units lower (at a reference density of 26.2σθ than was found in the summer of 1956.

This speech was given by the Prime Minister at the closing banquet of the Conference on the Reform of Federal Institutions in Quebec on March 30, 1984. He suggested that Reform is desirable because Canadian Federalism is capable of evolution and renewal. Canada needs institutions in which a national consensus on its fundamental options can be developed frankly and openly. The federal government's representativeness and its authority to speak and act in the name of all regions and of all Canadians must be strengthened. The proposed reform of the Upper House conducted by the Special joint Committee on Senate Reform indicates that provinces and regions should be represented adequately, not the provincial governments. These governments, because regional interests were not perceived to be adequately represented within the federal institutions, have had a tendency to present themselves as the only legitimate representatives of the regions. The idea of a second chamber elected directly by the people would enhance the independence and authority of senators in their role as regional representative. Mr. Trudeau indicates that the institutionalization of federal-provincial conferences ought to be looked at with the aim of harmonizing the policies of the two orders of government. This should establish coordination and effective management in areas of shared jurisdiction.

BackgroundTherapeutic options are limited for patients with liver metastases and hepatocellular carcinoma (HCC). Intratumoral and subcutaneous injections of CMP-001, a CpG-A TLR9 agonist packaged within a virus-like particle, have shown evidence of antitumor activity in patients with melanoma refractory to PD-1 blockade. In mice, CMP-001 intravenous distributes primarily to the liver, while CMP-001 subcutaneous is found mostly in local tissues and draining lymph nodes. The antitumor activity of CMP-001 intravenous and subcutaneous were compared with PD-1 blockade or sorafenib in two Hepa1-6 orthotopic mouse models of HCC.MethodsGroups of 10–15 C57BL/6J mice were orthotopically implanted with syngeneic murine hepatoma cells using two different models. Model 1 used 1.5 x 106 Hepa1-6 cells injected into the spleen following a partial hepatectomy; Model 2 used 1 x 106 Hepa1-6-Luc cells injected into the upper left lobe of intact liver. Treatment was initiated 3–7 days later with either CMP-001 intravenous or subcutaneous Q4-5Dx3-4 doses, PD-1 blocking antibody intraperitoneal Q3-4Dx2 (Bio X Cell clone RPM1-14), or sorafenib QD oral. Antitumor activity was assessed by tumor imaging, liver weight, and/or survival.ResultsCMP-001 was compared with PD-1 blocking antibody therapy in Model 1, the more aggressive model. All animals were sacrificed at day 15 due to institutional welfare requirements. Tumor growth inhibition (TGI) was assessed by comparison of liver weight to body weight ratios, which relative to untreated control mice showed that CMP-001 intravenous achieved 85% mean TGI compared with 63% mean TGI for CMP-001 subcutaneous and 15% mean TGI for PD-1 blocking antibody intraperitoneal (table 1). CMP-001 intravenous was compared to sorafenib oral in Model 2, which utilized an engineered Hepa1-6 cell line that expresses luciferase to enable noninvasive monitoring of liver tumor growth. CMP-001 intravenous was active, with a 67% mean TGI, and survival that was comparable to sorafenib (table 2; figure 1).Abstract 604 Table 1Abstract 604 Table 2Abstract 604 Figure 1ConclusionsIn orthotopic mouse models of HCC, the antitumor activity of CMP-001 intravenous was greater than PD-1 blockade and comparable to sorafenib. CMP-001 intravenous was more active than CMP-001 subcutaneous in this model, which we hypothesize is due to increased liver exposure with intravenous infusion. Antitumor activity of CMP-001 monotherapy may be increased by combining it with standard of care or other therapies, as observed relative to historical benchmarks in ongoing CMP-001 clinical trials in patients with melanoma. CMP-001 intravenous may be a promising treatment option for patients with primary or metastatic liver cancers.AcknowledgementsThis work was supported by Checkmate Pharmaceuticals. Studies were performed at Oncodesign Biotechnology (Dijon, France) and Crown Bioscience UK Ltd (Osgathorpe, UK) and National Research Council Canada (Ottawa, Ontario, Canada) and funded by Checkmate Pharmaceuticals.Ethics ApprovalAt Oncodesign Biotechnology, animal housing and experimental procedures were conducted according to French and European Regulations and the National Research Council Guide for the Care and Use of Laboratory Animals. The animal facility is authorized by the French authorities (Dijon: Agreement B21231011EA). The study and all animal procedures were approved by the Institutional Animal Care and Use Committee of Oncodesign (Oncomet) approved by French authorities (CNREEA agreement number 91). At Crown Bioscience, animal care and experimental procedures were compliant with the UK Animals Scientific Procedures Act 1986 (ASPA) in line with Directive 2010/63/EU of the European Parliament and the Council of 22 September 2010 on the protection of animals used for scientific purposes. At National Research Council Canada, animals were maintained in accordance with the guidelines of the Canadian Council on Animal Care, and all experimental procedures were performed in accordance with regulations and guidelines reviewed and approved by the NRC Human Health Therapeutics Ottawa Animal Care Committee.

2024 SPE President Terry Palisch is the vice president of technology and engineering at CARBO Ceramics in Richardson, Texas. He began his career with ARCO, during which he served 4 years in Algeria and 10 years as a senior petroleum engineer in Alaska. Palisch joined CARBO in 2004 and in his current position leads a team of technologists developing and championing new products and services and advising clients on completion and fracture optimization. Palisch has been an active SPE member serving in various roles, including past chairman of the SPE Dallas Section, past chair of the SPE Annual Technical Conference and Exhibition (ATCE) technical program and former SPE Completions Technical Director. He is an SPE Distinguished Member and received the award for Distinguished Service, as well as the SPE Mid‑Continent Regional Completions Optimization and Technology Award and the Regional Service Award. In 2013, he was named one of the Top 15 Best Engineers by the Texas Independent Producers and Royalty Owners Association, and in 2015 he was named the SPE Dallas Section Engineer of the Year. He has authored more than 50 SPE technical papers and holds several patents. Palisch holds a bachelor’s degree in petroleum engineering from University of Missouri‑Rolla (now Missouri University of Science and Technology) and was recently recognized as a Distinguished Alumnus. North America Regional Director Robert C. Martinez is president and CEO of Titan Rock Exploration & Production and president of Alpine Gas. He has more than 23 years of experience developing and optimizing oil and gas assets throughout the US, including conventional assets, unconventional horizontal development programs, and enhanced oil recovery projects. Middle East and North Africa Regional Director Mohamed Al Marzouqi is senior vice president of development at ADNOC Upstream Directorate. He has been with ADNOC since 2005. He joined ZADCO (ADNOC Offshore) as a petroleum engineer in field development to head the maximum-reservoir- contact (MRC) well-design team during which first production began through MRC wells from an artificial island. As a senior manager for reservoir development at ZADCO, he developed reservoir management strategy to redevelop a multibillion-dollar project in the Upper Zakum field through artificial islands. He led the team in the development of integrated reservoir management for ADNOC Group. Drilling Technical Director Robin Macmillan is the chief sales officer at Data Gumbo. He was previously senior vice president for business development at NOV, manager of Schlumberger drilling and measurements in Canada, and president at drill-bit company ReedHycalog. In his early career he worked in offshore and onshore drilling operations in several countries across North and Latin America, Africa, the Middle East, and Europe. He is the current vice president of drilling services and a member of the Executive Committee at the International Association of Drilling Contractors, where he is also Chair Emeritus of the Advanced Rig Technology Committee and a member of the Drilling Engineering Committee. Health, Safety, Environment, and Sustainability Technical Director Susan (Sue) Staley is the sustainability director for vPSI Group LLC where she leads the company’s sustainability practice. Prior to joining vPSI, she was the general manager of soil and groundwater technology at Shell and held various positions there during her 18-year tenure. Prior to Shell, she worked as a consultant at ERM. Staley has been an environmental and safety engineer for 30 years.

Objective: To systematically review the pharmacology, pharmacokinetics, clinical efficacy, and safety profile of ustekinumab to inform pharmacists and other healthcare professionals of this new biologic therapy for psoriasis. Data Sources: A search of PubMed/MEDLINE, EMBASE, and International Pharmaceutical Abstracts was performed through July 2009, limited to publications in English, using the search terms CNTO-1275, ustekinumab, interleukin-12, interleukin-23, and/or psoriasis to identify literature sources. References from the retrieved articles were also evaluated to identify relevant literature. An abstract from a Congress of the European Academy of Dermatology and Venereology and unpublished Phase 3 clinical trials in progress (using www.clinicaltrials.gov ) were also reviewed. The Food and Drug Administration, European Medicines Agency, and Health Canada Web sites were used to retrieve product monographs, regulatory guidances, and advisory committee briefing packets. Study Selection and Data Extraction: All available studies relevant to the pharmacology, pharmacokinetics, and clinical safety/efficacy of ustekinumab for the treatment of psoriasis were included, with preference for human data. Data Synthesis: Ustekinumab, an anti-interleukin-12/23 monoclonal antibody, achieved the primary endpoint of 75% reduction in the Psoriasis Area and Severity Index score in a large proportion of patients in the Phase 3 PHOENIX trials. Commensurate improvements were also seen in the Physician's Global Assessment and Dermatology Life Quality Index scores. These efficacy results were reproduced in the ACCEPT trial, demonstrating superiority of ustekinumab to etanercept. The frequency of adverse events was similar between ustekinumab and placebo; common adverse events reported included nasopharyngitis, upper respiratory tract infection, headache, arthralgia, cough, and injection site reactions. Phase 3 studies indicate that the optimal dosing appears to be 45 mg for patients weighing less than 100 kg or 90 mg for patients weighing more than 100 kg, with both doses administered subcutaneously. In these studies, the second dose was given 4 weeks after the first and then every 8–12 weeks thereafter, based upon response. Conclusions: Ustekinumab, a promising new therapy, reduces the extent and severity of psoriasis and was well tolerated in clinical trials. Ongoing clinical trials will allow clinicians to further assess the efficacy/safety profile of this novel biologic.

Introduction: Renal impairment (RI) is a common feature in multiple myeloma (MM) and an adverse predictor of survival. Anti-myeloma treatments that can also improve renal function in patients (pts) with MM are required. Isatuximab (Isa), a monoclonal CD38 antibody, is approved in combination with pomalidomide and dexamethasone (d), in the United States, the European Union, Canada, Australia, Switzerland, and Japan for the treatment of adult pts with relapsed/refractory MM who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor. IKEMA (NCT03275285) was a randomized, open-label, multicenter, Phase 3 study that demonstrated the benefit of adding Isa to carfilzomib (K) plus d vs Kd in pts with relapsed MM. This subgroup analysis of IKEMA examined efficacy, renal response, and safety in pts with RI. Methods: Pts with 1-3 prior lines of therapy were randomized 3:2 and stratified by number of prior lines and revised international staging system (R-ISS) stage to receive Isa-Kd or Kd. The Isa-Kd arm received Isa 10 mg/kg intravenously weekly for 4 weeks, then every 2 weeks thereafter. Both arms received recommended doses of Kd. Treatment continued until disease progression or unacceptable adverse events. Interim efficacy analysis was planned when 65% of the total expected progression-free survival (PFS) events determined by an Independent Response Committee were observed. RI was defined as estimated glomerular filtration rate ([eGFR]; using the Modification of Diet in Renal Disease equation) <60 mL/min/1.73m² at baseline. Complete renal response (CrR) was defined as improvement in eGFR from <50 mL/min/1.73m² at baseline to ≥60 mL/min/1.73m² (no RI) in at least one post-baseline assessment (International Myeloma Working Group recommendations), and was classified as durable if lasting ≥60 days. Results: A total of 302 pts (179 Isa-Kd; 123 Kd) were randomized. Pts with baseline eGFR as low as 15 mL/min/1.73m² (severe RI) were allowed to enroll. more pts with RI in the Isa-Kd arm (26.1%) vs Kd (16.2%). As expected, elderly pts had more RI. The median age in years (range) was 67 (39-86) for Isa-Kd vs 69 (49-90) for Kd among RI pts, and 64 (37-81) for Isa-Kd vs 62 (33-78) for Kd among pts with no RI. In RI pts, 60.5% vs 72.2% pts had ≥2 prior lines of therapy, 11.6% vs 16.7% had R-ISS stage III, and 20.9% vs 27.8% had high risk cytogenetics, in Isa-Kd vs Kd, respectively. More RI pts were still on treatment at the cut-off date in Isa-Kd (55.8%) vs Kd (16.7%). Median PFS for RI pts was not reached for Isa-Kd vs 13.4 months for Kd (HR 0.27; 95% CI 0.11-0.66), and not reached for both study arms among pts with no RI (HR 0.63; 95% CI 0.39-1.00). The overall response rate, ≥very good partial response rate, and minimal residual disease negativity for RI pts was higher with Isa-Kd than Kd: 93.0% vs 61.1%, 79.1% vs 44.4%, and 30.2% vs 11.1%, respectively. CrR accessed in pts with eGFR <50 mL/min/1.73m² (15.2% Isa-Kd vs 11.7% Kd) occurred more frequently in Isa-Kd (52%) vs Kd (30.8%), and these were durable in 32.0% vs 7.7% pts. The treatment exposure was higher in RI pts treated with Isa-Kd, with median number of cycles started and median duration of exposure being 20 vs 9 cycles and 81.0 vs 35.7 weeks in Isa-Kd vs Kd. In pts with RI, Grade ≥3 and serious treatment emergent adverse events (TEAEs) were reported in 79.1% (Isa-Kd) vs 77.8% (Kd) and 62.8% (Isa-Kd) vs 77.8% (Kd) pts, respectively. Grade 5 TEAEs (Isa-Kd, 0%; Kd, 11.1%) and TEAEs leading to treatment discontinuation were lower with Isa-Kd (Isa-Kd, 7.0%; Kd, 27.8%). End-stage renal disease on treatment occurred in 1.8% Isa-Kd vs 2.7% Kd pts. The most common TEAEs in RI pts in Isa-Kd vs Kd were diarrhea (41.9% vs 22.2%), upper respiratory tract infection (39.5% vs 27.8%), infusion reaction (37.2% vs 5.6%), hypertension (34.9% vs 27.8%), fatigue (34.9% vs 22.2%), and dyspnea (32.6% vs 11.1%). The most common Grade ≥3 TEAEs in RI pts in Isa-Kd vs Kd were hypertension (20.9% vs 22.2%) and pneumonia (11.6% vs 22.2%). Conclusions: The addition of Isa to Kd improved PFS and disease response in pts with RI, with a manageable safety profile, consistent with the benefit observed in the overall IKEMA study population. Also, more pts treated with Isa-Kd showed reversal of RI and durable renal responses compared with Kd. Finally, RI pts treated with Isa-Kd received twice the number of cycles and had a lower treatment discontinuation rate compared with Kd pts. Disclosures Martin: AMGEN: Research Funding; Sanofi: Research Funding; GSK: Consultancy; Seattle Genetics: Research Funding; Janssen: Research Funding. Moreau:Novartis: Honoraria; Sanofi: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Honoraria. Baker:Sanofi: Research Funding. Leleu:Karyopharm: Honoraria; Sanofi: Honoraria; Novartis: Honoraria; AbbVie: Honoraria; Amgen: Honoraria; Oncopeptide: Honoraria; Incyte: Honoraria; Merck: Honoraria; Carsgen: Honoraria; Janssen: Honoraria; BMS-celgene: Honoraria; GSK: Honoraria. Mohty:Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Stemline: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau. Leblanc:Celgene: Research Funding; Celgene Canada; Janssen Inc.; Amgen Canada; Takeda Canada: Membership on an entity's Board of Directors or advisory committees. Risse:Sanofi: Current Employment. Malinge:AIXIAL: Consultancy. Schwab:Sanofi: Current Employment. Dimopoulos:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau.

428 Background: Avelumab is a human anti‒PD-L1 IgG1 antibody approved in the US, Canada, and Israel for the treatment of locally advanced or metastatic urothelial carcinoma (mUC) progressed after platinum chemotherapy. In the JAVELIN Solid Tumor study, patients (pts) in various subgroups had a favorable objective response rate (ORR) with avelumab. Here, we report further post hoc analyses of safety and efficacy outcomes with avelumab in high-risk mUC subgroups. Methods: Pts with mUC that had progressed after platinum-based therapy in the JAVELIN Solid Tumor study were analyzed. Best overall response (per RECIST 1.1) was adjudicated by an independent review committee. ORR, disease control rate (DCR), progression-free survival (PFS), and adverse event (AE) profiles for pre-specified subgroups of high-risk pts were compared. Results: 242 pts with mUC received avelumab and were followed up for ≥2 years (data cutoff, Apr 2018). No difference was found in ORR between pts with renal insufficiency (creatine clearance [CrCl], <60 mL/min; n=107) and pts with CrCl ≥60 mL/min (n=131; 17.8% [95% CI: 11.0-26.3] vs 15.3% [95% CI: 9.6-22.6]) or between pts with upper (n=56) vs lower tract tumors (n=186; 14.3% [95% CI: 6.4-26.2] vs 17.2% [95% CI: 12.1-23.4]). ORR in pts with baseline liver metastases (n=83) was 6.0% (95% CI: 2.0-13.5) vs 22.0% (95% CI: 15.8-29.3) in pts without (n=159). ORR in elderly pts (≥75 years; n=68) was 25.0% (95% CI: 15.3-37.0) vs 13.2% (95% CI: 8.6-19.2) in younger pts (n=174). ORR in pts with albumin ≥35 g/L (n=197) was 19.8% (95% CI: 14.5-26.1) vs 2.2% (95% CI: 0.1-11.8) in pts with <35 g/L (n=45). Except for the albumin levels and age subgroups (where the trend in ORR was not confirmed), subgroups showed DCR and PFS that were consistent with ORR trends. AE profiles did not exhibit any higher risk of adverse effects in these subgroups. Conclusions: Responses to avelumab occurred in select assessed subgroups previously defined as poor prognostic or high risk, suggesting that immunotherapy may achieve comparable efficacy irrespective of factors such as site of disease and renal status; no difference in safety profiles was identified. Clinical trial information: NCT01772004.

Abstract Background Venous thrombotic events (VTE) in children are related to central venous catheters and occur predominantly in the upper venous system. In routine clinical practice, ultrasound (US) is the most frequently used imaging technique for diagnosis of VTE in children because of its ease of use and non-invasiveness. However, US is known to be relatively insensitive for detection of VTE in the central upper venous system. Magnetic resonance venography (MRV) is a promising alternative as MRV can comprehensively image the central venous system, is minimally invasive and does not involve radiation. However, MRV involves high technical and logistic demands, and requires sedation in young children. Objectives To compare the feasibility and diagnostic accuracy of US and MRV for diagnosis of central venous catheter related VTE in children. Methods Study Design: Cross-sectional diagnostic study. Study population: Children 0-<18 years of age with a central venous catheter in place for any reason were recruited prospectively and consisted of i) children who are asymptomatic for VTE: children who were screened for central venous catheter-related VTE within 20-60 days of catheter placement ii) children who are symptomatic for VTE: children presenting with signs and symptoms of central venous catheter related VTE within 7 days of symptom onset (all study-related imaging tests were completed within this time period). Children were excluded in case of i) systemic anticoagulant or antiplatelet therapy, and ii) inability to undergo contrast MRV. Imaging tests: Each participant had three imaging tests performed i) Doppler compression US ii) MRV without contrast iii) MRV with gadolinium contrast. All imaging studies were performed within 48 hours of each other. Data collection included clinical and demographic information on each subject, imaging and video documentation of each US and MRV. Central Adjudication Committee: All imaging studies were blinded and independently reviewed and interpreted by a central adjudication committee for the presence or absence of VTE. Outcomes: The two main study outcomes were 1) Feasibility of performing each test: assessed by a) the number of children who completed each diagnostic study and b) the number of evaluable studies; and 2) Diagnostic accuracy of each diagnostic test: assessed by the proportion of VTE identified by the respective test in relation to the total number of VTE identified by any imaging modality. Results A total of 152 children were enrolled from 24 centers in 9 countries: Argentina, Brazil, Mexico, United States, Canada, United Kingdom, Netherlands, Austria and Germany. The median age (range) for children was 11 years (2 months to 17 years). Fourteen (9.2%) children had clinical symptoms of VTE. One hundred and thirty three (88%) children had US completed, 113 (74%) had MRV without contrast and 113 (74%) had MRV with contrast. 18 subjects withdrew from the study before any test was performed for various reasons. Adjudication and analysis are ongoing, and will be completed by October 14th, 2013. Therefore, final results regarding the feasibility and diagnostic accuracy of each test will be available at the time of presentation. Conclusion We have completed the largest and most comprehensive study to date comparing the feasibility and diagnostic accuracy of currently available non-invasive imaging modalities for detecting central venous catheter related VTE in children. Ultrasound demonstrated better feasibility than MRV, however, MRV still proved feasible in nearly three-quarters of pediatric subjects and was performed without sedation in individuals as young as 2 months old. The overall feasibility and diagnostic accuracy of each test will be reported after final adjudication and analysis are complete. The study findings will be used to formulate an effective pediatric diagnostic algorithm for diagnosis of central venous catheter-related VTE. The algorithm will be used as guidance for clinical practice as well as outcome assessments for clinical trials of antithrombotic agents in children. Disclosures: Male: Bristol Myer Squibb: Consultancy. Yee:Bristol Myer Squibb: Research Funding. Loewe:Bristol Myer Squibb: Consultancy. Krishnamurthy:Koninklijke Philips NV: Research Funding; Bristol Myer Squibb: Consultancy. Chalmers:Bristol Myer Squibb: Consultancy. Newburger:Merck: Consultancy; Janssen Pharmacutical: Consultancy; Bristol Myer Squibb: Consultancy. Ramirez:Bristol Myer Squibb: Employment. Portman:Bristol Myer Squibb: Employment. Mitchell:Bristol Myer Squibb: Consultancy; Eisai: Consultancy; Boehringer Ingelheim: Consultancy.

Abstract Background Spontaneous bacterial peritonitis (SBP) is a lethal complication of decompensated cirrhosis carrying a 90% mortality rate when left untreated. Despite AASLD recommendations, there is a practice gap regarding fluid cell count (FCC) collection during paracentesis. Aims We initiated prospective quality improvement (QI) project to improve FCC collection in an ambulatory care setting from a baseline of 78% to a goal of 100% compliance between September 11, 2022 and April 17, 2023. Methods We examined the effects of a quality improvement initiative in 233 adult patient encounters with cirrhosis undergoing paracentesis in an ambulatory setting located within a quaternary care centre in Toronto, Canada within the study timeframe. Using a multidisciplinary approach, the quality improvement initiatives included focused groups, education regarding AASLD guidelines, development of a paracentesis bundle, and streamlining workflow process. Descriptive statistics were collected. Statistical analysis using run charts and p-charts were conducted using QI Macros. Approval was obtained from the QI Review Committee at the institution where this QI initiative took place. Results Baseline adherence for collecting ascitic FCC per paracentesis procedure was 78%. Inconsistencies during process mapping such as variations in documentation, printing FCC labels and consistency in FCC collection were identified as root causes. Thus, bedside paracentesis bundles were introduced to standardize process and improve workflow. Post-intervention, the FCC rate increased marginally to 79.6% with no special cause variation identified (Figure 1). Subgroup analysis demonstrated FCC collection rates of 100% amongst registered nurse (RN) and nurse practitioners (NP), 97% amongst resident physicians, and 92% amongst attending physicians. Subsequently, another subgroup analysis was completed demonstrating 97% FCC collection rate amongst general hepatology group, while 40% FCC rate amongst specialty hepatology group. Overall rate of SBP was 1.62% (N=3). Conclusions This prospective QI study revealed a gap in guidance pertaining to the role of ascitic fluid cell count collection in patients with cirrhosis undergoing paracentesis in ambulatory settings. Further studies ascertaining rationale for not sending FCC may be helpful in elucidating why there is a gap in clinical practice. Additionally conducting studies in ambulatory settings to assess FCC collection's impact on morbidity and mortality will provide vital evidence and clarity for the role of FCC in this vulnerable patient group. Figure 1: P-chart demonstrating percentage FCC Collection per week from September 11, 2022 to April 17, 2023. UCL indicates upper control limit; CL, center line; LCL, lower Control Limit. Funding Agencies Toronto Centre for Liver Disease funded the MSc QI program for Mary Sedarous (writer) who completed this study as her MSc QI project.

Probiotics are microorganisms exerting beneficial effects on the host. They can be ingested through foods or supplements and their inclusion in these products is regulated in Canada by the Health Canada Health Products and Food Branch. The aim of this article is to summarize current evidence from randomized controlled trials and guidelines from Health Canada, the World Health Organization, and internationally recognized expert committees in the hope that it will help practitioners and professionals recommending probiotics to healthy and diseased patients, with a focus on the Canadian setting. From a general perspective, probiotics can be recommended for prevention of diseases that are associated to altered intestinal ecology. Specifically, they can be recommended for prevention of upper respiratory tract infections and pouchitis, for prevention and management of necrotizing enterocolitis, bacterial vaginosis and antibiotic associated diarrhea, including Clostridium difficile infection, and for treatment of atopic eczema in cow’s milk allergy and of infectious diarrhea. Additional substantiated probiotic benefits include prevention of hypercholesterolemia, management of constipation, reduction of recurrent urinary tract infections, improvement of irritable bowel syndrome symptoms, and reduction of antibiotics side effects in Helicobacter pylori eradication. Because probiotics are generally recognized as safe and can be removed with antimicrobial agents, their use should be considered in patients of all ages.

Abstract Introduction: Outcomes of patients (pts) with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) remain dismal, with 5-year survival &lt;20%. CD22 is expressed on lymphoblasts in &gt;90% of pts with B-ALL and is an established therapeutic target. ADCT-602 is an antibody drug conjugate composed of a humanized monoclonal antibody directed against CD22 and conjugated to SG3199, a pyrrolobenzodiazepine (PBD) dimer cytotoxin. In preclinical studies, ADCT-602 demonstrated potent anti-tumor activity in mouse models of B-cell malignancies. We present here interim data from an ongoing Phase 1/2 trial evaluating ADCT-602 in pts with R/R B-ALL (NCT03698552). Methods: This is an investigator-initiated Phase 1/2 trial of ADCT-602 monotherapy in pts with R/R B-ALL. The primary objective of the Phase 1 part is to assess the safety and determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of ADCT-602. The primary objective of Phase 2 is to evaluate efficacy (CR/CRi rate). Secondary objectives include duration of response (DOR), progression-free survival (PFS) and overall survival (OS), and characterize the pharmacokinetic (PK) profile of ADCT-602. Eligible pts must be ≥18 years of age with R/R B-ALL with bone marrow blasts ≥5%. CD22 must be expressed in ≥20% blasts. Pts must have adequate organ function (creatinine ≤1.5 mg/dL; ALT and AST ≤2 times upper limit of normal (ULN), ≤5 times ULN if there is liver or bone involvement; total bilirubin ≤1.5 times ULN; LVEF ≥45%). In part 1, pts were assigned to treatment according to a 3+3 dose-escalation design. ADCT-602 was initially given IV once every 3 weeks; recently, based on the PK data, the administration schedule was amended to weekly infusions. Results: From November 2018 to June 2021, 14 pts (8 male, 6 female) with B-ALL have been treated with ADCT-602. The median age was 39.5 years (range, 22-82) and pts had received a median of 5 (range, 2-7) prior therapies [inotuzumab ozogamicin 10/14 (71%); blinatumomab 13/14 (93%); venetoclax 10/14 (71%); CD19 CAR 5/14 (36%)]. Seven (7/14, 50%) pts had a prior allogeneic stem cell transplant (allo-SCT), including 3 pts with 2 prior allo-SCT. The median pretreatment bone marrow blasts were 70.5% (range, 16-95). The median CD22 expression on blasts was 90.5% (range, 33.6-99.9). A total of 11 pts were treated in the Q3week schedule [30µg/kg, n=3; 60µg/kg, n=4; 90µg/kg, n=4]. As the PK data (shown below) indicated rapid clearance of the antibody, the trial was amended to allow for weekly dosing and 3 pts have been treated at 30µg/kg weekly dose level. No pt had a DLT. Two pts (one each at 60µg/kg and 90µg/kg every 3 weeks schedule) did not complete the DLT window due to rapid disease progression and were taken off treatment prior to day 28. One pt (in the weekly schedule) had grade 4 thrombocytopenia possibly related to ADCT-602. No pt had veno-occlusive disease. Two pts achieved MRD-negative remission. One pt was 35-year-old with R/R B-ALL (complex karyotype, NRAS mutation) with several prior lines of therapy (HCVAD, pegasparaginase-based therapy, allo-SCT, inotuzumab, POMP). Baseline bone marrow blasts were 87% with 99.9% CD22 expression. Pt received ADCT-602 at 30µg/kg Q3week schedule and achieved MRD negative CRp after Cycle 1 which improved to MRD negative CR after Cycle 2. He received a total of 6 cycles of ADCT-602 before transitioning to second allo-SCT. Another pt was 22-year-old with R/R B-ALL (complex karyotype) with multiple prior therapies (including 2 prior allo-SCT, CD19 CAR-T, inotuzumab, blinatumomab, pegasparaginase, venetoclax) received ADCT-602 at 30µg/kg weekly schedule. Baseline bone marrow blasts were 24% with 97% CD22 expression. Pt achieved MRD negative CRp after Cycle 1 and is currently receiving Cycle 2. PK data, available for 9 pts treated at every 3-week schedule [30 mcg/kg, n=3; 60 mcg/kg, n=4; 90 mcg/kg, n=2] showed rapid clearance of antibody with mean apparent half-life of &lt;1 day during Cycle 1. This supported transitioning ADCT-602 administration to the weekly dosing. Conclusions: In this Phase 1 study in pts with very heavily pretreated R/R B-ALL with a median of 5 prior lines of therapy and high baseline bone marrow tumor burden, single-agent ADCT-602 was well tolerated with no DLTs noted. Two pts achieved MRD-negative remission. Dose escalation in the weekly schedule continues and 2 additional dose levels (40µg/kg weekly and 50µg/kg weekly) are planned. Disclosures Jain: Aprea Therapeutics: Research Funding; Janssen: Honoraria; ADC Therapeutics: Honoraria, Research Funding; TG Therapeutics: Honoraria; Incyte: Research Funding; Cellectis: Honoraria, Research Funding; Beigene: Honoraria; Adaptive Biotechnologies: Honoraria, Research Funding; Servier: Honoraria, Research Funding; Pfizer: Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Fate Therapeutics: Research Funding; Precision Biosciences: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Pharmacyclics: Research Funding. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Konopleva: Sanofi: Other: grant support, Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Calithera: Other: grant support, Research Funding; Ablynx: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Cellectis: Other: grant support; Stemline Therapeutics: Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Forty Seven: Other: grant support, Research Funding; KisoJi: Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Agios: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Ascentage: Other: grant support, Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding. Pemmaraju: Celgene Corporation: Consultancy; LFB Biotechnologies: Consultancy; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Samus: Other, Research Funding; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Sager Strong Foundation: Other; Plexxicon: Other, Research Funding; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; DAVA Oncology: Consultancy; Protagonist Therapeutics, Inc.: Consultancy; Cellectis S.A. ADR: Other, Research Funding; Daiichi Sankyo, Inc.: Other, Research Funding; CareDx, Inc.: Consultancy; Aptitude Health: Consultancy; Springer Science + Business Media: Other; Roche Diagnostics: Consultancy; MustangBio: Consultancy, Other; Incyte: Consultancy; Affymetrix: Consultancy, Research Funding; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Thompson: Amgen: Other: Institution: Honoraria, Research Grant/Funding; Gilead: Other: Institution: Advisory/Consultancy, Honoraria; Adaptive Biotechnologies: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding, Expert Testimony; Genentech: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; AbbVie: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Pharmacyclics: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Janssen: Consultancy, Honoraria. Short: Astellas: Research Funding; AstraZeneca: Consultancy; Jazz Pharmaceuticals: Consultancy; NGMBio: Consultancy; Novartis: Honoraria; Takeda Oncology: Consultancy, Research Funding; Amgen: Consultancy, Honoraria. Kadia: Genentech: Consultancy, Other: Grant/research support; Pfizer: Consultancy, Other; AstraZeneca: Other; Cure: Speakers Bureau; BMS: Other: Grant/research support; Jazz: Consultancy; Liberum: Consultancy; Sanofi-Aventis: Consultancy; Pulmotech: Other; Astellas: Other; Genfleet: Other; Ascentage: Other; Cellonkos: Other; Novartis: Consultancy; Dalichi Sankyo: Consultancy; Amgen: Other: Grant/research support; Aglos: Consultancy; AbbVie: Consultancy, Other: Grant/research support. Borthakur: GSK: Consultancy; Protagonist: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees; University of Texas MD Anderson Cancer Center: Current Employment; ArgenX: Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; Ryvu: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Daver: Daiichi Sankyo: Consultancy, Research Funding; Novimmune: Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Novartis: Consultancy; Pfizer: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Glycomimetics: Research Funding; Trillium: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Hanmi: Research Funding; FATE Therapeutics: Research Funding; Trovagene: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. DiNardo: Takeda: Honoraria; ImmuneOnc: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding; Agios/Servier: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Forma: Honoraria, Research Funding; Foghorn: Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. Ravandi: Jazz: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Taiho: Honoraria, Research Funding; Prelude: Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Research Funding; Novartis: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria, Research Funding. Kantarjian: Astellas Health: Honoraria; Daiichi-Sankyo: Research Funding; Ascentage: Research Funding; Pfizer: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Immunogen: Research Funding; Aptitude Health: Honoraria; NOVA Research: Honoraria; Amgen: Honoraria, Research Funding; KAHR Medical Ltd: Honoraria; Astra Zeneca: Honoraria; Ipsen Pharmaceuticals: Honoraria; BMS: Research Funding; Novartis: Honoraria, Research Funding; Jazz: Research Funding; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. OffLabel Disclosure: ADCT-602 is not approved for B-ALL

Abstract Background: Mutations in the RAS/RAF/MEK/ERK pathway result in resistance to several acute myeloid leukemia (AML) therapies, including hypomethylating agents (HMAs) plus venetoclax. Trametinib is an oral MEK inhibitor that has been studied as monotherapy in relapsed/refractory (R/R) AML with KRAS/NRAS mutations. Preclinical studies have suggested synergy between venetoclax and trametinib in RAS-mutated AML. We therefore sought to evaluate the combination of azacitidine, venetoclax, and trametinib in patients (pts) with R/R AML with Ras pathway-activating mutations. Methods: In this phase II study, adult pts with R/R AML or higher-risk R/R MDS or CMML (intermediate-2 or high-risk by the International Prognostic Scoring System with ≥10% blasts) harboring a Ras pathway-activating mutation involving HRAS/NRAS/KRAS, KIT, BRAF, CBL, PTPN11 or NF1 were eligible). Pts were required to have a performance status ≤2, total bilirubin ≤2.5 x upper limit of normal (ULN), ALT/AST ≤ 3 x ULN, and creatinine clearance ≥30 mL/min. In cycle 1, pts received azacitidine 75 mg/m 2 SC/IV on days 1-7, venetoclax on days 1-28 (100mg on day 1, 200mg on day 2, 400mg on days 3-28), and trametinib 2mg PO on days 1-28. Bone marrow examination was performed on day 21 and if blasts &lt;5% or aplastic marrow, then venetoclax was held. For cycles 2 and beyond, azacitidine 75 mg/m 2 SC/IV was given on days 1-7, venetoclax was given for daily on days 1 - 21 and trametinib 2mg was given continuously. Results: Between 8/2020 and 5/2021, 16 pts were treated. Baseline characteristics are shown in Table 1. The median age was 67 years (range, 28-84 years) and 6 pts (38%) were ≥75 years of age. This was a very heavily pretreated population, and the median number of prior therapies was 4 (range, 1-7). All pts had received prior HMAs, including 13 pts (81%) who had received prior HMA plus venetoclax. Eight pts (50%) had undergone prior hematopoietic stem cell transplant (HSCT). Fourteen pts (88%) had adverse-risk disease, including 6 (38%) with complex karyotype and 3 (19%) with TP53 mutation. Excluding Ras pathway mutations, ASXL1 was the most common co-mutation and was present in 50% of pts. Overall, 4 pts (25%) responded (1 with CR, 1 with CRi and 2 with MLFS). The only pt with CMML responded and attained CR. Two of the 3 pts (67%) who had not previously received HMA plus venetoclax responded (1 CR and 1 MLFS); in contrast, only 2 of the 13 pts (15%) who had previously received HMA plus venetoclax responded (1 CRi and 1 MLFS). Three of the 4 responders had diploid karyotype and one NRAS mutation; the other pt had complex karyotype and an NF1 mutation. Of the 3 responding pts with a NRAS mutations, 2 showed a dramatic decrease in their respective NRAS variant allelic frequencies (0.15 to 0.05 and 0.51 to 0.02). In addition to the 4 pts with formal responses, 4 pts (25%) had a bone marrow blast reduction of ≥50%, including 1 pt with prior treatment with HMA plus venetoclax who had blast reduction from 26% to 6% and who continued on study for 5.5 months. The median duration of follow-up is 7.4 months. One pt who achieved MLFS relapsed after 2 months of remission. The other 3 pts remain in remission. Two of these pts remain on study with ongoing remissions of 3 and 8 months, and the other pt underwent HSCT and has ongoing remission of 7 months. The median overall survival (OS) of the entire cohort was 2.7 months and the 6-month OS rate was 25% (Figure 1A). The median OS for responders and non-responders was not reached and 1.7 months, respectively (P=0.02; Figure 1B). The most common non-hematologic adverse events of any grade were diarrhea (88%) and nausea (63%). Grade 3 non-hematologic adverse events possibly related to study treatment included: mucositis (n=3), diarrhea (n=1), and decreased ejection fraction (EF) (n=1). Six pts (38%) required dose reduction or temporary cessation of trametinib due to mucositis (n=2), retinopathy (n=1), decreased EF (n=1), rash (n=1), and diarrhea (n=1). Conclusion: In this heavily pretreated pt population with poor-risk disease with Ras pathway-activating myeloid malignancies, the triplet combination of azacitidine, venetoclax and trametinib resulted in a response rate of 25%. Two of 3 pts without prior exposure to HMA plus venetoclax responded, and although response rate was modest (15%) in pts with prior HMA plus venetoclax, the activity in this population suggests potential benefit of adding trametinib in these pts. Figure 1 Figure 1. Disclosures Ravandi: Taiho: Honoraria, Research Funding; Prelude: Research Funding; Agios: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Xencor: Honoraria, Research Funding; Novartis: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding. Pemmaraju: Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Daiichi Sankyo, Inc.: Other, Research Funding; Springer Science + Business Media: Other; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Plexxicon: Other, Research Funding; Incyte: Consultancy; Affymetrix: Consultancy, Research Funding; CareDx, Inc.: Consultancy; Protagonist Therapeutics, Inc.: Consultancy; Sager Strong Foundation: Other; LFB Biotechnologies: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Samus: Other, Research Funding; MustangBio: Consultancy, Other; Aptitude Health: Consultancy; Cellectis S.A. ADR: Other, Research Funding; Roche Diagnostics: Consultancy; DAVA Oncology: Consultancy; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Konopleva: Rafael Pharmaceuticals: Other: grant support, Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Calithera: Other: grant support, Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Forty Seven: Other: grant support, Research Funding; Cellectis: Other: grant support; Agios: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Sanofi: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Stemline Therapeutics: Research Funding; Ascentage: Other: grant support, Research Funding; KisoJi: Research Funding; Ablynx: Other: grant support, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights. Loghavi: Abbvie: Current equity holder in publicly-traded company; Curio Sciences: Honoraria; Gerson Lehrman Group: Consultancy; Guidepoint: Consultancy; Peerview: Honoraria; Qualworld: Consultancy. Borthakur: Astex: Research Funding; ArgenX: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; University of Texas MD Anderson Cancer Center: Current Employment; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Protagonist: Consultancy; Ryvu: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Daver: Pfizer: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Novimmune: Research Funding; Novartis: Consultancy; Trillium: Consultancy, Research Funding; Hanmi: Research Funding; Sevier: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Glycomimetics: Research Funding; Genentech: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Jain: Fate Therapeutics: Research Funding; Genentech: Honoraria, Research Funding; TG Therapeutics: Honoraria; Aprea Therapeutics: Research Funding; Beigene: Honoraria; Servier: Honoraria, Research Funding; Pfizer: Research Funding; Precision Biosciences: Honoraria, Research Funding; Incyte: Research Funding; Janssen: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; Cellectis: Honoraria, Research Funding; Adaptive Biotechnologies: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Pharmacyclics: Research Funding. Kadia: Genfleet: Other; Ascentage: Other; AstraZeneca: Other; Sanofi-Aventis: Consultancy; Cellonkos: Other; Astellas: Other; Pulmotech: Other; Pfizer: Consultancy, Other; Novartis: Consultancy; Liberum: Consultancy; Jazz: Consultancy; Genentech: Consultancy, Other: Grant/research support; Dalichi Sankyo: Consultancy; Cure: Speakers Bureau; BMS: Other: Grant/research support; Amgen: Other: Grant/research support; Aglos: Consultancy; AbbVie: Consultancy, Other: Grant/research support. Kantarjian: BMS: Research Funding; Pfizer: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Astellas Health: Honoraria; Amgen: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Ascentage: Research Funding; Astra Zeneca: Honoraria; Jazz: Research Funding; Immunogen: Research Funding; Novartis: Honoraria, Research Funding; Aptitude Health: Honoraria; NOVA Research: Honoraria; KAHR Medical Ltd: Honoraria; Ipsen Pharmaceuticals: Honoraria; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Short: Amgen: Consultancy, Honoraria; Takeda Oncology: Consultancy, Research Funding; Astellas: Research Funding; AstraZeneca: Consultancy; Novartis: Honoraria; Jazz Pharmaceuticals: Consultancy; NGMBio: Consultancy. OffLabel Disclosure: Trametinib is a MEK inhibitor working in the RAS/RAF pathway. In patients with relapse/refractory AML with mutations in this pathway, downstream inhibition might provide an avenue for treatment.

Abstract Background: Pevonedistat is a first-in-class inhibitor of NEDD8-activating enzyme that catalyzes the rate-limiting step of protein neddylation, a critical step in the degradation of cellular proteins that occurs upstream of the proteasome. The combination of azacitidine plus pevonedistat has resulted in high response rates and durable remissions in both myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), particularly in secondary AML (s-AML). Preclinical studies suggest that pevonedistat synergizes with venetoclax through neutralization of Mcl-1, providing rationale for the triplet combination of azacitidine, venetoclax and pevonedistat. Methods: In this phase I/II study, adult patients (pts) with newly diagnosed s-AML, including pts with therapy-related AML (t-AML) or AML with MDS-related changes, who were unsuitable for intensive chemotherapy were eligible. Pts were required to have a performance status ≤2, total bilirubin ≤ upper limit of normal (ULN), ALT/AST ≤2.5 x ULN, and creatinine clearance ≥30 mL/min. In cycle 1, pts received azacitidine 75 mg/m 2 SC/IV on days 1-7, venetoclax on days 1-28, and pevonedistat 20 mg/m 2 IV on days 1, 3 and 5 on a 28-day schedule. Venetoclax dose ranged from 200mg to 400mg daily during the phase I dose escalation. For cycles 2 and beyond, venetoclax was given on days 1-21. Results: Between 3/2019 and 5/2021, 28 pts were treated (3 pts at venetoclax 200mg daily and 25 pts at 400mg daily). Baseline characteristics are shown in Table 1. The median age was 74 years (range, 61-80), and 12 pts (43%) were ≥75 years of age. The study population was enriched with pts with poor-risk features, including 19 pts (68%) with adverse-risk cytogenetics, 14 (50%) with prior hypomethylating (HMA) or chemotherapy exposure for preceding hematologic malignancy, and 8 (29%) with TP53 mutation. The overall response rate (CR+CRi+MLFS) was 71%, and the CR+CRi rate was 64%. Thirteen pts (46%) achieved CR as best response, 5 (18%) achieved CRi, and 2 (7%) achieved MLFS. Among the 18 pts who achieved CR/CRi, 8 (44%) achieved MRD negativity by multiparameter flow cytometry. Responses were observed across subgroups, including in 8/14 pts (57%) with prior HMA/chemotherapy exposure, 6/8 pts (75%) with TP53 mutation, 12/19 pts (63%) with poor-risk cytogenetics, and 8/9 pts (89%) without non-poor-risk cytogenetics. With a median follow-up of 13.4 months (range 0.4 to 26.3+ months), the median overall survival (OS) was 8.2 months, and the median relapse-free survival was 7.5 months (Figure 1). The median OS for pts with poor-risk and non-poor cytogenetics was 7.9 and 18.0 months, respectively; for pts with and without prior HMA/chemotherapy exposure was 6.2 and 8.9 months, respectively; and for pts with inv(3) AML, TP53-mutated AML, and non-inv(3)/non-TP53-mutated AML was 3.8, 8.9, and 18.0 months, respectively. Four pts (14% of the entire cohort, 20% of responding pts) proceed to hematopoietic stem cell transplantation (HSCT), 3 of whom are still alive and 1 with inv(3) who relapsed post-HSCT and died from progressive AML. The combination was overall well-tolerated with myelosuppression as expected with the combination of HMA plus venetoclax in AML. The median number of cycles received was 2 (range, 1-13 cycles). Non-hematologic grade ≥3 adverse events occurring in ≥2 pts included infection or neutropenic fever in 18 pts (61%), hypophosphatemia in 8 pts (29%), hyperglycemia, hyperbilirubinemia and ALT/AST elevation in 3 pts each (11%), and pneumonitis, acute kidney injury, hypokalemia and vomiting in 2 pts each (7%). One pt developed multiorgan failure on cycle 1, day 1 of therapy, with transaminase elevation, hyperbilirubinemia, renal failure and hyperferritinemia; this pt recovered with holding therapy and supportive care. Hypophosphatemia, which has previously been reported with pevonedistat, was easily managed with oral or intravenous phosphorus supplementation. The 4-week and 8-week mortality rates were 7% and 14%, respectively. Conclusions: The combination of azacitidine, venetoclax and pevonedistat was safe and effective in a very poor-risk population of pts with s-AML, half of whom had prior HMA or chemotherapy exposure for antecedent hematologic malignancy. A randomized study evaluating azacitidine and venetoclax ± pevonedistat (NCT04266795) is ongoing and will help to clarify the potential role of pevonedistat in the frontline treatment of AML. Figure 1 Figure 1. Disclosures Short: AstraZeneca: Consultancy; Jazz Pharmaceuticals: Consultancy; NGMBio: Consultancy; Astellas: Research Funding; Novartis: Honoraria; Takeda Oncology: Consultancy, Research Funding; Amgen: Consultancy, Honoraria. Alvarado: Daiichi-Sankyo: Research Funding; Jazz Pharmaceuticals: Research Funding; FibroGen: Research Funding; BerGenBio: Research Funding; MEI Pharma: Research Funding; Sun Pharma: Consultancy, Research Funding; CytomX Therapeutics: Consultancy; Astex Pharmaceuticals: Research Funding. Konopleva: KisoJi: Research Funding; Ascentage: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; Ablynx: Other: grant support, Research Funding; Cellectis: Other: grant support; Forty Seven: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Calithera: Other: grant support, Research Funding; Sanofi: Other: grant support, Research Funding; Stemline Therapeutics: Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Yilmaz: Pfizer: Research Funding; Daiichi-Sankyo: Research Funding. Jain: Genentech: Honoraria, Research Funding; Cellectis: Honoraria, Research Funding; Precision Biosciences: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; Pfizer: Research Funding; Adaptive Biotechnologies: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Aprea Therapeutics: Research Funding; Janssen: Honoraria; Incyte: Research Funding; Servier: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Fate Therapeutics: Research Funding; Beigene: Honoraria; TG Therapeutics: Honoraria; Pharmacyclics: Research Funding; AbbVie: Honoraria, Research Funding. Borthakur: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ryvu: Research Funding; ArgenX: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; University of Texas MD Anderson Cancer Center: Current Employment; GSK: Consultancy; Protagonist: Consultancy. DiNardo: ImmuneOnc: Honoraria, Research Funding; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Foghorn: Honoraria, Research Funding; Forma: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Novartis: Honoraria; Agios/Servier: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. Daver: Astellas: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Glycomimetics: Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Amgen: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; Hanmi: Research Funding; Novimmune: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Issa: Syndax Pharmaceuticals: Research Funding; Novartis: Consultancy, Research Funding; Kura Oncology: Consultancy, Research Funding. Pemmaraju: MustangBio: Consultancy, Other; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Aptitude Health: Consultancy; Samus: Other, Research Funding; Plexxicon: Other, Research Funding; Sager Strong Foundation: Other; CareDx, Inc.: Consultancy; Cellectis S.A. ADR: Other, Research Funding; Daiichi Sankyo, Inc.: Other, Research Funding; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Springer Science + Business Media: Other; Pacylex Pharmaceuticals: Consultancy; Celgene Corporation: Consultancy; Roche Diagnostics: Consultancy; DAVA Oncology: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; LFB Biotechnologies: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Incyte: Consultancy; Affymetrix: Consultancy, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy. Sasaki: Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding. Ravandi: AstraZeneca: Honoraria; Jazz: Honoraria, Research Funding; Taiho: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Honoraria, Research Funding; Novartis: Honoraria; Prelude: Research Funding. Kadia: Genfleet: Other; Cure: Speakers Bureau; Genentech: Consultancy, Other: Grant/research support; Amgen: Other: Grant/research support; Dalichi Sankyo: Consultancy; Jazz: Consultancy; Novartis: Consultancy; Liberum: Consultancy; Aglos: Consultancy; Pfizer: Consultancy, Other; AbbVie: Consultancy, Other: Grant/research support; Pulmotech: Other; BMS: Other: Grant/research support; Astellas: Other; Sanofi-Aventis: Consultancy; AstraZeneca: Other; Cellonkos: Other; Ascentage: Other. Andreeff: Breast Cancer Research Foundation: Research Funding; Aptose: Consultancy; Daiichi-Sankyo: Consultancy, Research Funding; Karyopharm: Research Funding; Novartis, Cancer UK; Leukemia & Lymphoma Society (LLS), German Research Council; NCI-RDCRN (Rare Disease Clin Network), CLL Foundation; Novartis: Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Consultancy; Senti-Bio: Consultancy; Oxford Biomedica UK: Research Funding; Syndax: Consultancy; AstraZeneca: Research Funding; ONO Pharmaceuticals: Research Funding; Amgen: Research Funding; Reata, Aptose, Eutropics, SentiBio; Chimerix, Oncolyze: Current holder of individual stocks in a privately-held company; Medicxi: Consultancy. Bose: Pfizer: Research Funding; Constellation Pharmaceuticals: Research Funding; Novartis: Honoraria; Sierra Oncology: Honoraria; Kartos Therapeutics: Honoraria, Research Funding; Blueprint Medicines: Honoraria, Research Funding; CTI BioPharma: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Incyte Corporation: Honoraria, Research Funding; Astellas: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding. Kantarjian: Ipsen Pharmaceuticals: Honoraria; Amgen: Honoraria, Research Funding; Precision Biosciences: Honoraria; Astellas Health: Honoraria; Astra Zeneca: Honoraria; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; KAHR Medical Ltd: Honoraria; Aptitude Health: Honoraria; Pfizer: Honoraria, Research Funding; Ascentage: Research Funding; NOVA Research: Honoraria; BMS: Research Funding; Jazz: Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Taiho Pharmaceutical Canada: Honoraria. Cortes: Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Bio-Path Holdings, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sun Pharma: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, Astellas, Novartis, Pfizer, Takeda, BioPath Holdings, Incyte: Consultancy, Research Funding.

Abstract Background: Ponatinib and blinatumomab are both highly effective in Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). The combination of these two agents may lead to deep and durable responses, thereby reducing the need for both chemotherapy and allogeneic stem cell transplant (ASCT) in first remission. Methods: In this phase II study, adults with newly diagnosed (ND) Ph+ ALL, relapsed/refractory (R/R) Ph+ ALL, or chronic myeloid leukemia in lymphoid blast phase (CML-LBP) were eligible. Patients (pts) were required to have a performance status of ≤2, total bilirubin ≤2x the upper limit of normal (ULN), and alanine aminotransferase and aspartate aminotransferase ≤3x the ULN. Pts with uncontrolled cardiovascular disease or clinically significant central nervous system (CNS) comorbidities (except for CNS leukemia) were excluded. Pts received up to 5 cycles of blinatumomab as a continuous infusion at standard doses. Ponatinib 30mg daily was given during cycle 1. Ponatinib was decreased to 15mg daily once a complete molecular response (CMR) was achieved. After completion of blinatumomab, ponatinib was continued for at least 5 years in responding pts. Twelve doses of prophylactic intrathecal chemotherapy with alternating cytarabine and methotrexate were administered. For pts with ND Ph+ ALL, the primary endpoint was the CMR rate. For pts with R/R Ph+ ALL, the primary endpoint was the overall response rate (defined as the composite of CR/CRi). Results: Between February 2018 and July 2021, 43 were treated (24 ND, 14 R/R and 5 CML-LBP). Baseline characteristics are shown in Table 1. The median age of the ND and R/R Ph+ ALL cohorts were 60 years (range, 34-83) and 38 years (range, 24-61), respectively. BCR-ABL1 transcripts were p190 in 67% of pts in the ND cohort and 93% in the R/R cohort. 43% of pts in the R/R Ph+ ALL cohort were in salvage 2 or beyond. Among 32 pts evaluable for morphologic response, all but 1 pt (97%) responded. Notably, the one non-responding pt had R/R Ph+ ALL and had previously received ponatinib in an earlier salvage regimen. The CR/CRi rate was 100% for ND pts, 91% for R/R pts, and 100% CML-LBP pts. 84% of responding pts achieved CMR (91% in the ND cohort, 91% in the R/R cohort, and 40% in the CML-LBP cohort). The CMR rates after 1 cycle were 64%, 82% and 20% in these 3 groups, respectively. Among 10 pts in the ND cohort who had peripheral blood PCR for BCR-ABL1 evaluated on day 7 of cycle 1, 3 (30%) had already achieved CMR at this early timepoint; 5 out of 13 evaluable patients (38%) had achieved CMR by days 14-21 of cycle 1 The median follow-up is 9 months (range, 1-38+ months). Among the 24 pts in the ND cohort, 1 pt died in CR, and the rest are all in ongoing response without HSCT in first remission, with a median CR duration of 8 months (range, 1-36+ months). The estimated 2-year EFS and OS for the ND cohort is 95% (Figure 1). Among the 14 pts in the R/R cohort, 2 are too early for response evaluation, 1 did not respond, 4 underwent ASCT (3 of whom are still alive without relapse and 1 of whom relapsed post-ASCT and died), 2 did not undergo ASCT and subsequently relapsed, 1 died in CR, and 4 are in ongoing response without ASCT. The estimated 2-year EFS and OS for the R/R cohort are 53% and 39%, respectively (Figure 1). Among the 5 pts in the CML-LBP cohort, 2 relapsed (1 of whom converted to myeloid immunophenotype) and 3 are in ongoing response without ASCT. The combination treatment was well-tolerated, and most side effects were grade 1-2 and were consistent with the known toxicity profile of the two agents individually. Two pts discontinued ponatinib due to toxicity (1 due to stroke and 1 due to DVT). No pts discontinued blinatumomab due to toxicity. No early deaths were observed. Conclusion: The chemotherapy-free combination of ponatinib and blinatumomab is a safe and effective regimen in both ND and R/R Ph+ ALL, as well as in CML-LBP. Given the particularly favorable outcomes of pts with ND Ph+ ALL who were not transplanted in first remission, these data suggest that this regimen may serve as an effective transplant-sparing regimen in this population. Figure 1 Figure 1. Disclosures Short: Novartis: Honoraria; Jazz Pharmaceuticals: Consultancy; AstraZeneca: Consultancy; NGMBio: Consultancy; Astellas: Research Funding; Takeda Oncology: Consultancy, Research Funding; Amgen: Consultancy, Honoraria. Kantarjian: Ascentage: Research Funding; BMS: Research Funding; AbbVie: Honoraria, Research Funding; Astra Zeneca: Honoraria; Pfizer: Honoraria, Research Funding; Jazz: Research Funding; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; Astellas Health: Honoraria; Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Ipsen Pharmaceuticals: Honoraria; KAHR Medical Ltd: Honoraria; Aptitude Health: Honoraria; NOVA Research: Honoraria; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Konopleva: Ascentage: Other: grant support, Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; KisoJi: Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; Stemline Therapeutics: Research Funding; Cellectis: Other: grant support; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Calithera: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; Sanofi: Other: grant support, Research Funding; Ablynx: Other: grant support, Research Funding; Forty Seven: Other: grant support, Research Funding. Jain: Aprea Therapeutics: Research Funding; Precision Biosciences: Honoraria, Research Funding; Beigene: Honoraria; TG Therapeutics: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Pfizer: Research Funding; Adaptive Biotechnologies: Honoraria, Research Funding; Janssen: Honoraria; ADC Therapeutics: Honoraria, Research Funding; Fate Therapeutics: Research Funding; Servier: Honoraria, Research Funding; Incyte: Research Funding; Genentech: Honoraria, Research Funding; Cellectis: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Pharmacyclics: Research Funding; AbbVie: Honoraria, Research Funding. Ravandi: Prelude: Research Funding; Agios: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; AstraZeneca: Honoraria; Amgen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria; Xencor: Honoraria, Research Funding; Taiho: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding. Borthakur: University of Texas MD Anderson Cancer Center: Current Employment; Protagonist: Consultancy; Ryvu: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; ArgenX: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sasaki: Novartis: Consultancy, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees. Issa: Kura Oncology: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Syndax Pharmaceuticals: Research Funding. Alvarado: Daiichi-Sankyo: Research Funding; Jazz Pharmaceuticals: Research Funding; MEI Pharma: Research Funding; FibroGen: Research Funding; CytomX Therapeutics: Consultancy; BerGenBio: Research Funding; Astex Pharmaceuticals: Research Funding; Sun Pharma: Consultancy, Research Funding. Pemmaraju: Celgene Corporation: Consultancy; Protagonist Therapeutics, Inc.: Consultancy; Roche Diagnostics: Consultancy; Cellectis S.A. ADR: Other, Research Funding; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; CareDx, Inc.: Consultancy; Sager Strong Foundation: Other; Plexxicon: Other, Research Funding; Incyte: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Springer Science + Business Media: Other; Aptitude Health: Consultancy; Daiichi Sankyo, Inc.: Other, Research Funding; Affymetrix: Consultancy, Research Funding; Samus: Other, Research Funding; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Clearview Healthcare Partners: Consultancy; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; MustangBio: Consultancy, Other; LFB Biotechnologies: Consultancy; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. DiNardo: Takeda: Honoraria; Novartis: Honoraria; ImmuneOnc: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding; Forma: Honoraria, Research Funding; Foghorn: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Agios/Servier: Consultancy, Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. OffLabel Disclosure: Blinatumomab and ponatinib as frontline therapy for Ph+ ALL

IntroductionSubglottic stenosis (SGS) is a rare condition that results from progressive narrowing of the upper airways. Outcomes and treatment options depend on the benign or complex nature of the stenosis. Treatment options for SGS include surgery and endoscopic techniques. The main endoscopic techniques used are dilation and laser resection. Observational and retrospective studies suggest that endoscopic laser resection may be more effective than dilation. We, therefore, aimed to compare the effectiveness of dilation and laser resection in preventing recurrence of SGS.Methods and analysisAERATE (dilAtion vs laser Endoscopic Resection in subglottic trAcheal sTEnosis) is a multicentre, investigator-initiated, randomised controlled trial, comparing endoscopic dilation to endoscopic laser resection for simple benign SGS (less than 1 cm long without underlying cartilaginous damage) referred for endoscopic treatment (first treatment or recurrence). The study will be conducted in three centres in France and one in Canada with other centres from France and Canada expected to join. The primary outcome is the recurrence rate of stenosis at 2 years. Recurrence is defined as having a new onset of symptoms along with a stenosis of more than 40% (confirmed by bronchoscopy) requiring a new procedure. A sample size of 100 patients is calculated for the primary endpoint assuming a 10% recurrence rate in the laser resection group and 33% in the dilation group with a statistical significance level of 5%, a power of 80%.Ethics and disseminationThis study is approved by local and national ethics committees as required. Results will be published, and trial data will be made available.Trial registration numberNCT04719845.

Abstract 1. Background Central venous catheters (CVCs) are a leading cause of upper extremity deep vein thrombosis (UE DVT). There is little data on patients with acute leukemia (AL). Long term CVCs are required for chemotherapy in AL. Concomitant severe thrombocytopenia makes anticoagulation for CVC related thrombosis a challenge. Incidence of UE DVT has been reported to be increased in those with peripherally inserted central venous catheters (PICC lines) vs those with centrally inserted lines. 2. Aims Our objective is to compare the incidence rate of VTE in leukemia inpatients with a PICC vs centrally-inserted CVC. 3. Methods We reviewed 420 charts for AL inpatients requiring a PICC line admitted to Hematology at the University of Alberta Hospital between 2003-2013. Baseline patient characteristics were recorded. All venous thromboembolic events were objectively confirmed on imaging studies. Incidence of catheter associated thrombosis was calculated. 4. Results 420 patients were identified. We present the preliminary results of the 337 patients that met our inclusion criteria, and received at least one PICC line insertion. 305 (90%) had AML, 144 (43%) were smokers, 126 (37.4%) had cardiovascular risk factor, and only 14 (4.2%) had previous VTE. Overall, there were 634 PICC line insertions, with the 5FR dual lumen being the most commonly used PICC line (80%). Out of the 634 insertions, there were 65 (10%) new ipsilateral upper extremity DVTs, 54 (83%) of which developed acutely (<1month), and 44 (68%) in thrombocytopenic patients (platelet<50). 7 (1.1%) and 15 (2.4%) patients developed recurrent and concurrent VTEs, respectively. There was an incidence of 1.85 DVT per 1000 catheter days. 5. Conclusions The incidence rate of DVT in our AL patients is higher than predicted for a general cancer patient population. This data will be compared to a similar cohort of AL inpatients presently being reviewed, who received a centrally-inserted CVC. Updated results will be included accordingly. Determining factors that are associated with a lower risk of DVT in this high bleeding risk population will be important to optimize patient care. Disclosures Wu: Leopharma: Membership on an entity's Board of Directors or advisory committees; Pfizer Canada: Membership on an entity's Board of Directors or advisory committees.

BackgroundNon-communicable diseases (NCDs) are the leading cause of death globally. In 2014, the United Nations committed to reducing premature mortality from NCDs, including by reducing the burden of healthcare costs. Since 2014, the Prospective Urban and Rural Epidemiology (PURE) Study has been collecting health expenditure data from households with NCDs in 18 countries.MethodsUsing data from the PURE Study, we estimated risk of catastrophic health spending and impoverishment among households with at least one person with NCDs (cardiovascular disease, diabetes, kidney disease, cancer and respiratory diseases; n=17 435), with hypertension only (a leading risk factor for NCDs; n=11 831) or with neither (n=22 654) by country income group: high-income countries (Canada and Sweden), upper middle income countries (UMICs: Brazil, Chile, Malaysia, Poland, South Africa and Turkey), lower middle income countries (LMICs: the Philippines, Colombia, India, Iran and the Occupied Palestinian Territory) and low-income countries (LICs: Bangladesh, Pakistan, Zimbabwe and Tanzania) and China.ResultsThe prevalence of catastrophic spending and impoverishment is highest among households with NCDs in LMICs and China. After adjusting for covariates that might drive health expenditure, the absolute risk of catastrophic spending is higher in households with NCDs compared with no NCDs in LMICs (risk difference=1.71%; 95% CI 0.75 to 2.67), UMICs (0.82%; 95% CI 0.37 to 1.27) and China (7.52%; 95% CI 5.88 to 9.16). A similar pattern is observed in UMICs and China for impoverishment. A high proportion of those with NCDs in LICs, especially women (38.7% compared with 12.6% in men), reported not taking medication due to costs.ConclusionsOur findings show that financial protection from healthcare costs for people with NCDs is inadequate, particularly in LMICs and China. While the burden of NCD care may appear greatest in LMICs and China, the burden in LICs may be masked by care foregone due to costs. The high proportion of women reporting foregone care due to cost may in part explain gender inequality in treatment of NCDs.

Introduction:Hepatic venous occlusive disease (VOD) is a well-described early complication of allogeneic hematopoietic stem cell transplant (HSCT). The disease presents with elevated bilirubin, hepatomegaly, right upper quadrant pain, ascites and weight gain. Multi organ failure (MOF) can also occur, mainly renal and pulmonary failure, in severe cases. The incidence, pathogenesis, risk factors, and treatment of VOD remain poorly defined. Purpose:We aimed to determine the incidence of, risk factors, treatment patterns and resource utilization associated with VOD in Canada. Methods:Using the Cell Therapy and Transplant Canada (CTTC) database, which collects data from 15 stem cell transplant programs across Canada, a retrospective observational study was performed. Using patient demographics, disease and transplant characteristics, and the Center for International Blood & Marrow Transplant Research (CIBMTR) Form 2553 which collects information on patients diagnosed with VOD, data was collected. All allogeneic transplants performed on both children and adults between 2013 and 2019 were included in the analysis. Children and adults were analyzed as two separate cohorts. Results:The total incidence of VOD was 64/2507 (2.55%). The incidence of VOD was 27/464 (5.82%) in children and 24/2030 (1.18%) in adults. Risk factors for VOD for children and adults are shown in Tables 1 and 2, respectively. The most common treatments for VOD in children and adults were defibrotide (74.1% and 29.2%, respectively), diuretics (70.4% and 62.5%, respectively) and ursodiol (48.0% and 63.6%, respectively). The mean intensive care unit (ICU) visit duration and hospitalization in children with VOD was 7.0 days and 37.1 days, respectively. The mean ICU visit duration and hospitalization in adults with VOD was 8.2 days and 37.1 days, respectively. There were no differences in overall survival, relapse rates or non-relapse mortality between VOD patients and non-VOD patients in both children and adults. Discussion:Between 2013 and 2019, the incidence of VOD in allogeneic HSCT in Canada was 2.55%. This is consistent with recent reports from other countries including from the CIBMTR and a report from the United States at 3.3% and 5.4%, respectively. An unexpected finding was the difference in incidence between children and adults. Possible explanations for this include younger age being an actual risk factor for VOD, increased clinical vigilance amongst pediatric clinicians, reporting bias, alternative diagnoses because of more hepatic comorbidities in adults or a more obvious clinical presentation of VOD in children. This requires further investigation. Further to this, a higher proportion of children diagnosed with VOD received defibrotide than did adults diagnosed with VOD. It is unclear why this occurred. The significant risk factors identified in our study are similar to previously published risk factors for VOD. Although, comparative data with non-VOD patients was not available in this data set, VOD patients in both the pediatric and adult populations have longer hospitalizations than historical controls which have an average hospitalization of 23.6 days. No survival or relapse differences were found in our data however VOD cases were not divided into VOD and VOD-MOF. VOD-MOF has been associated with significant mortality of &gt;80%. Weaknesses of our study include its retrospective nature, potential for reporting bias, variable reporting quality from multiple centres and lack of uniform diagnostic criteria for VOD. Conclusion:The incidence and risk factors for VOD in 15 Canadian HSCT centres are similar to previous reports from other countries. Children made up a higher proportion of VOD patients and a high proportion of children received defibrotide. Further study of the resource utilization associated with VOD is required. Acknowledgements:Veronique Baribeau and Jean Lachaine of PeriPharm Inc. for data analysis and Jazz Pharmaceuticals for funding, study design, data analysis and editorial contributions. Disclosures Paulson: Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Abstract Background The median age at diagnosis of MM is 69 years. Randomized, controlled studies on the safety and effectiveness of AHCT are lacking in those > 70 years of age and many patients are considered “ineligible” on the basis of age. We analyzed survival (OS) outcomes of 11,430 MM patients from US and Canada receiving AHCT after high dose melphalan (MEL) between 2008 -2011 reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). The relative efficacy of AHCT was compared in 3 cohorts; those aged ≥70 years (Cohort 1, n=946) vs. those 60-69 years (Cohort 2, n= 4666) and vs. 18-59 years (Cohort 3, n=5818). A statistically representative subset of 1279 patients was then analyzed in further detail to compare relapse, progression free survival (PFS) and non-relapse mortality (NRM). Results The median ages in group 1, 2, and 3 were 72, 64 and 53 years, respectively with an upper age of 89 years. The older age cohort 1 was composed of a higher proportion of male patients, IgA MM, US patients (vs. Canada) and had worse Karnofsky scores (KPS < 100) and co morbidity scores (HCTCI ≥ 2), (all p values <0.05). The older age cohort was less likely to be transplanted within the first year of diagnosis and more likely to have MEL dose reduction (MEL <180 mg/m2 in 42%). Disease status at AHCT did not vary between groups with >40% of patients at least in a very good partial remission (≥VGPR) at transplant in all 3 cohorts. After a median follow up in survivors of 2 years, median OS has not been reached and 3 year OS was inferior for the older cohort at 72% (95% CI, 67-76%), 75% (73-77%), 78% (76-79%) in cohorts 2 and 3 respectively (Figure 1). In multivariate analysis, increasing age was associated with inferior OS (p=0.0006, Fig 1). Hazard ratio for death was 1.12 for cohort 2 vs. 3, 1.35 for cohort 1 vs. 3 and 1.2 for cohort 1 vs. 2. Other significant predictors of lower OS were higher HCTCI score, lower KPS, longer (>12mo) interval from diagnosis to AHCT and inferior disease status (<VGPR) at AHCT. Further analyses were performed to identify the contribution of relapse, NRM and post relapse survival. NRM within the first year was 0% for the older cohort and 2% for the other 2 cohorts, likely reflecting careful patient selection. Relapse risk at 3 years was similar between cohorts 1,2 and 3 at 63% (48-74%), 51% (55-66%) and 56% (51-60%) respectively. PFS at 3 years was 33% (21-46%), 38% (33-43%) and 42% (37-46%) respectively. In multivariate analyses, increasing age was NOT associated with higher risk of relapse, NRM or lower PFS. KPS <80 was associated with higher risk of relapse, NRM and lower PFS. Other significant risks for relapse and lower PFS were longer interval from diagnosis to AHCT and a < VGPR disease state prior to AHCT. Post relapse survival was significantly worse for the older cohort (p=0.03, Figure 2). Post relapse survival was significantly worse with increasing age. For cohorts 1, 2 and 3 at 2 years, it was 54% vs. 50% and 63% and at 3 yrs 25% vs. 37% and 49% respectively (p=0.03, Fig 2). Conclusions AHCT although performed less frequently in the older MM patient, offers equivalent efficacy in and is associated with low NRM. Survival differences are driven partly by higher co-morbidities and lower post relapse survival. Myeloma related outcomes are similar when appropriate older patients are treated with aggressive therapy. Disclosures: Gasparetto: Onyx: Membership on an entity’s Board of Directors or advisory committees; Millennium (2012): Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Celgene ( 2012): Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Lonial:Sanofi: Consultancy; BMS: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Millennium: Consultancy; Onyx: Consultancy. Hari:Celgene: Consultancy; Onyx: Consultancy.

Abstract Abstract 745 Background: The optimum chemotherapy combination prior to autologous stem cell transplantation (ASCT) for patients with relapsed or refractory aggressive non-Hodgkin lymphomas (NHL) has not been defined. We previously established the safety and efficacy of outpatient treatment with GDP in a phase II study (Crump et al, Cancer 2004) leading to this phase III trial testing the hypothesis that GDP is as effective and less toxic than standard DHAP, and potentially associated with better quality of life (QoL) and less resource utilization. Methods: Patients (pts) with relapsed/refractory aggressive NHL were stratified by IPI score at relapse (0, 1 vs 2,vs >=3 risk factors), immunophenotype (B vs T cell), disease status following initial treatment (response duration < 1yr vs duration > 1yr vs no response/PD) and prior treatment with rituximab (R); and were randomized to 2–3 21-day cycles of G 1000 mg/m2 day 1 & 8, D 40 mg day 1–4, P 75 mg/m2day 1 or standard DHAP. Pts with CR, PR (or SD, per institutional policy) proceeded to PBSC collection and ASCT. The protocol was amended 11/2005 to include R with GDP or DHAP for pts with CD20+ lymphoma. Co-primary endpoints were response rate (RR) after 2 cycles (CR/CRu/PR) according to 1999 International Workshop criteria, and transplantation rate; FDG-PET was not used to determine response. Using a non-inferiority design, the study was powered to exclude a 10% difference in RR between GDP and DHAP (α 0.05, power 80%). Other endpoints included toxicity, event-free (EFS) and overall survival (OS), QoL and an economic analysis. FACT-G, FACT-CNS and FACT-LYM instruments and validated lymphoma-specific questions were used to assess QoL. Results of a second randomization to post-ASCT rituximab consolidation vs observation for pts with CD20+ lymphoma will be reported subsequently. Results: From 8/2003 to 11/2011, 619 pts were enrolled at 52 centres in Canada, Italy, Australia and the US (GDP 310 DHAP 309). Pt characteristics: median age 55 yrs (28.4% >60 y); histology: DLBCL 71%, PTCL 4%, ALCL 4%, transformed 14%; IPI risk factors: 0,1: 38%, 2: 29%; >3: 33%; elevated LDH 59%; prior R treatment 67%; refractory to initial therapy 31%; all baseline characteristics were balanced between treatment arms. In the intention to treat (ITT) population, RR for GDP was 45.2% and for DHAP 44.0%. The upper boundary of the one-sided 95.6% confidence interval for the difference in RRs was 5.67% and did not cross the pre-specified 10% non-inferiority boundary, meaning protocol-stated criteria for declaring GDP non-inferior to DHAP were met (p=0.005); results were robust when assessed using a per-protocol analysis. 362/554 pts (65.3%) with B cell NHL received R with protocol therapy: RRs were similar between arms in pts with and without prior R exposure, and with and without R added to GDP or DHAP. The transplantation rate was 51.8% for GDP vs 49.3% for DHAP (per protocol analysis; p = 0.49); 6 pts in each arm could not mobilize adequate PBSCs. At a median follow-up of 53 months, 4 year EFS was 25.6% and 26.1% (HR 0.99, p=0.95) and 4 year OS 39.0% and 39.1% (HR 1.03, p=0.78) for GDP and DHAP, respectively. Pts receiving GDP experienced less grade 3–4 toxicity (47 vs 61%, p=0.0003), including febrile neutropenia (9 vs 23%, p<0.0001), platelet transfusion during the first 2 treatment cycles (18% vs. 32%, p < 0.0001) and AEs requiring hospitalization (18 vs 30%, p=0.0005). One pt in each arm died from infection during GDP/DHAP therapy (0.3%). Compared to baseline, superior mean and greater-than-minimally-important change scores for QoL were seen during and/or after 2 treatment cycles in the GDP group when assessed using FACT-LYM, the Trial Outcome Index for FACT-LYM and the lymphoma-specific subscale. Stratified by important baseline characteristics, in univariate analysis no variables were associated with response; in multivariate analysis, ECOG PS, stage and number of sites of disease were significantly associated with OS; age and stage were associated with EFS. Conclusion: The response rate to GDP is not inferior to the standard regimen DHAP prior to ASCT for aggressive lymphomas and GDP resulted in similar rates of transplantation, EFS and OS. GDP can be given in the outpatient setting with significantly less toxicity, superior QoL scores and reduced need for hospitalization. This study supports the use of GDP as a new standard in practice and in future studies focused on improving salvage therapy approaches. Disclosures: Crump: Roche Canada: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Gemcitabine for treatment of lymphoma. Kuruvilla:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Macdonald:Roche Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kukreti:Roche: Honoraria. Kouroukis:Roche: Honoraria. Meyer:Dr. Meyer has received honoraria from Lilly re role on a DSMC: Honoraria. Olney:Roche: Consultancy.

Abstract Introduction Hepatic VOD/SOS is a progressive, potentially life-threatening complication early post-HSCT, or of nontransplant chemotherapy. VOD/SOS diagnosis has been based on Baltimore (≤21 days post-HSCT and bilirubin ≥2 mg/dL plus ≥2 of: hepatomegaly, ascites, weight gain ≥5%) or modified Seattle (≤20 days post-HSCT and ≥2 of: bilirubin >2 mg/dL, hepatomegaly or right upper quadrant pain, weight gain [>5% in defibrotide studies]) criteria. Recent European Society of Blood and Marrow Transplantation (EBMT) VOD/SOS guidelines require elevated bilirubin only for adults diagnosed ≤21 days post-HSCT (the literature suggests bilirubin <2 mg/dL before Day +21 is uncommon) but not for adults with late-onset (diagnosis >21 days post-HSCT) or pediatric patients (~30% of pediatric patients present with anicteric VOD/SOS [ie, bilirubin <2 mg/dL]). EBMT notes that hyperbilirubinemia may be a late finding in the progression of VOD/SOS. Defibrotide is approved to treat hepatic VOD/SOS with renal and/or pulmonary dysfunction post-HSCT in the United States and Canada, and to treat severe hepatic VOD/SOS post-HSCT in patients aged >1 month in the European Union. This post hoc analysis examines incidence of VOD/SOS without elevated bilirubin, and survival in defibrotide-treated, post-HSCT patients in the T-IND program (2007-2016). Methods Prior to US approval, defibrotide was available through the T-IND expanded-access program. The original protocol required VOD/SOS post-HSCT diagnosed per Baltimore criteria (which require hyperbilirubinemia) or biopsy, and multi-organ dysfunction (MOD). The protocol was amended to include patients without MOD (2009) and with VOD/SOS per modified Seattle criteria (which do not require hyperbilirubinemia; 2012). Patients received defibrotide 25 mg/kg/day (6.25 mg/kg q6h) recommended for ≥21 days. Results Of 991 patients in the T-IND with VOD/SOS post-HSCT and recorded bilirubin level at diagnosis, 190 (19%) had bilirubin <2 mg/dL (breakdown by subgroups in the Table), and 801 (81%) had bilirubin ≥2 mg/dL. Of those with bilirubin <2 mg/dL, 133 were pediatric patients aged ≤16 years (24% of all post-HSCT pediatric patients with recorded bilirubin [n=564]), and 57 were adult patients aged >16 years (13% of all post-HSCT adult patients with recorded bilirubin [n=427]). Diagnosis by Day +21 post HSCT (ie, not late onset) was recorded for 135/190 (71%) patients with bilirubin <2 mg/dL (107/133 [80%] pediatric patients; 28/57 [49%] adults). In the overall post-HSCT group treated with defibrotide in the T-IND (n=1000; with and without elevated bilirubin at diagnosis, including 9 patients without bilirubin measurement at diagnosis), Kaplan-Meier estimated Day +100 survival was 58.9% (95% confidence interval [CI], 55.7%-61.9%). Kaplan-Meier estimated Day +100 survival was 85.6% (95% CI, 79.7%-89.9%) for the 190 patients with bilirubin <2 mg/dL at diagnosis and 52.3% (95% CI, 48.7%-55.7%) for the 801 patients with bilirubin ≥2 mg/dL (survival by age subgroups in the Figure). In the overall population of patients with bilirubin <2 mg/dL, 61.1% and 18.4% of patients had ≥1 treatment emergent adverse event (TEAE) and ≥1 treatment related adverse event (TRAE), respectively, and 21.1% had ≥1 hemorrhage event; for patients with bilirubin ≥2 mg/dL: 73.8% had ≥1 TEAE, 21.7% had ≥1 TRAEs, and 31.1% had ≥1 hemorrhage event. Conclusions: In the T-IND, 19% of post-HSCT patients with VOD/SOS had bilirubin <2 mg/dL at diagnosis, including 24% of children. Accordingly, 190 patients would not have been diagnosed if hyperbilirubinemia was a required criterion. Moreover, enrollment prior to 2012 required hyperbilirubinemia (or biopsy), so this percentage may understate the incidence of anicteric VOD/SOS. Of patients with bilirubin <2 mg/dL, 80% of pediatric patients and 49% of adults were diagnosed with VOD/SOS by Day +21 post-HSCT, suggesting that anicteric VOD/SOS may develop in this timeframe not only in pediatric patients but also in a sizeable number of adult patients. Defibrotide showed higher survival in patients with bilirubin <2 mg/dL compared to those with levels ≥2 mg/dL. These results compare favorably with the overall study findings, suggesting that treatment before the onset of hyperbilirubinemia may lead to better outcomes. The safety profile of the T-IND was similar to that of previous studies of defibrotide for the treatment of VOD/SOS. Support: Jazz Pharmaceuticals. Disclosures Corbacioglu: Gentium: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria. Kernan:National Cancer Institute: Research Funding. Pagliuca:Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gentium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Ryan:Jazz Pharmaceuticals: Employment, Other: Stock and stock options. Tappe:Jazz Pharmaceuticals: Employment, Other: Stock and stock options. Richardson:Karyopharm: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Chloroethene (vinyl chloride) does not occur naturally in nature. It is obtained exclusively by chemical synthesis. It is a gas under normal pressure and temperature conditions. At 40-70 °C, it polymerizes to form polyvinyl chloride (PVC). It is a large-volume compound. Its annual global production exceeds 40 million t / year. About 98% of the total production is used to produce polyvinyl chloride (PVC) and copolymers. Chloroethene is also used in the synthesis of 1,1,1-trichloroethane (methyl chloroform) Exposure to chloroethene occurs during its synthesis and polymerization as well as during plastification and processing of polymers and copolymers that take place in many industries, including plastics, footwear, rubber and pharmaceutical industries. The main route of occupational exposure to chloroethene is inhalation. After cessation of exposure, the levels of chloroethene in blood fall sharply. Absorption of the compound through the respiratory tract is very rapid. Deposition of chloroethene in the body is limited due to its rapid metabolism and excretion. The largest amount of absorbed chloroethene accumulates in the liver, where it undergoes biotransformation. The intermediate products of chloroethene metabolism, chloroethylene oxide and 2-chloroacetaldehyde, are the most reactive metabolites of this compound. The detoxification process takes place in the liver and relies on their conjugation with glutathione. As a result of further metabolism, final metabolites are formed which are excreted mainly with urine. In low concentrations, this is the main route of excretion. With the increase in the exposure concentration, the amount of chloroethene excreted by the lungs in the unchanged form increases. Chloroethene has a very low acute toxicity, which has been found in both volunteer and animal studies. In volunteers as a result of acute inhalation exposure to high concentrations, only neurological and psychiatric disorders were observed. In animal studies, depressive effects on the central nervous system were observed, and histopathological examination revealed damage of liver, lung, kidney, heart and blood clotting disorders. In workers chronically exposed to high concentrations of chloroethene, a syndrome of vinyl chloride disease was found, which includes symptoms of Raynaud's syndrome (pain, numbness and tingling in the upper and lower limbs, cold feeling in the limbs), pseudoscleroderma, acroosteolysis, allergic dermatitis, peripheral polyneuropathy, neurological disorders, as well as hepatotoxic effects. In animal studies chronically exposed by inhalation to chloroethene, the hepatotoxic effect of the compound is well documented. This effect has been found at a relatively low concentration of 26 mg / m3 (10 ppm). In addition, there is evidence that chloroethene affects the vascular and respiratory system. The effects of the compound on bones, kidneys, spleen, blood and animal skin are less well documented. Chloroethene has mutagenic / genotoxic properties, as observed in in vitro tests both with and without metabolic activation, and in in vivo tests. In in vitro tests on bacterial strains, the activity of chloroethene was much stronger with the participation of an exogenous metabolic system. Epidemiological studies in workers exposed to chloroethene showed an increased incidence of chromosomal aberrations, sister chromatid exchanges, micronuclei in lymphocytes and DNA damage in peripheral blood lymphocytes. The highest frequency of genotoxic effects was observed among operators of polymerization reactors subject to periodic exposure to very high concentrations of chloroethene. Chloroetene has been classified as a carcinogen by the International Agency for Research on Cancer, IARC (Group 1) and the European Union (Category 1A). It was concluded that there was sufficient evidence of a carcinogenic effect of chloroethene in humans and sufficient evidence of carcinogenicity in experimental animals. Carcinogenic effect of chloroethene has a genotoxic basis and results from the formation of reactive metabolites, mainly chloroethylene oxide and 2-chloroacetaldehyde, which reacting with DNA act mutagenically on somatic cells, mainly endothelial cells and thus play a significant role in the etiology of angiosarcoma. Epidemiological studies have demonstrated a significant causal link between exposure to chloroethene and the incidence of hepatic cancers: angiosarcoma of the liver (ASL) and hepatocellular carcinoma (HCC). Epidemiological studies have shown a correlation between the number of deaths from liver tumors and the duration and magnitude of exposure and the length of latency, which in the case of ASL ranges from 10 to> 30 years. Carcinogenic effects of chloroethene on the lungs, brain, lymphatic and circulatory systems, skin and digestive system (cancers other than liver cancer) are less documented and ambiguous. There are reports of the effect of chloroethene on the reproductive functions of women and men and the defects of their offspring. Existing data do not provide unambiguous evidence of teratogenicity and reproductive effects in the case of occupational exposure. In animal studies, chloroethene affected fertility and prenatal development of rats at high concentrations, with a NOAEL of 2860 mg / m3 (1100 ppm). Available data indicate that the target organ of chloroethene toxicity in chronic exposure in humans is the liver, and the critical effect of exposure is the development of liver tumors. In epidemiological studies, the effect of occupational cumulative exposure dose (CED) on the development of angiosarcoma of the liver (ASL) is best documented. The SCOEL Scientific Committee using PBPK models estimated the risk of ASLs at 3 • 10-4 as a result of 40 years of occupational exposure to chloroethene in a concentration of 2.6 mg / m3 (1 ppm). Taking into account the above calculations, as well as the accepted level of occupational risk for carcinogens in the range from 10-4 to 10-3, the TWA of chloroethene at the level of 2.6 mg / m3 (1 ppm) has been proposed. This means an increase in the incidence of 3 liver cancers (ASL) per 10,000 people. There is no substantive basis to determine a short-term exposure limit (STEL) and acceptable concentration in biological material (DSB). It is proposed to label the compound as "Carc. 1A "- carcinogen category 1A. The proposed value is in line with the value adopted by ACGIH and in Canada and the binding value proposed by SCOEL for this compound, as well as the binding value included in Directive of the European Parliament and of the Council (EU) 2017/2398 of 12 December 2017 amending Directive 2004/37 / EC on the protection of workers from the risks related to exposure to carcinogens or mutagens at work.

Abstract Background: Guadecitabine (G) is a next generation subcutaneous (SC) hypomethylating agent (HMA) resistant to degradation by cytidine deaminase which results in prolonged in vivo exposure to the active metabolite decitabine. We conducted a large global randomized phase 3 study (ASTRAL-2) of G vs TC in AML patients who were either refractory to or relapsed (r/r) after prior anthracycline-based intensive chemotherapy with or without hematopoietic cell transplant (HCT). Methods: r/r AML patients were randomized to G (60 mg/m 2 SC/d for 10 days in first 1-2 cycles followed by 5-day cycles Q 28 days) vs Treatment Choice (TC). TC were preselected prior to randomization to either low intensity (LI) treatment; high intensity (HI) chemotherapy; or Best Supportive Care (BSC). LI choices were other HMAs of azacitidine or decitabine, or low-dose Ara-C (LDAC) at their standard doses. HI choices were high-dose Ara-C (HiDAC), MEC, or FLAG± Ida combination chemotherapy at standard doses. Primary endpoint was overall survival (OS) based on ITT analysis with secondary endpoints including 12 and 24-month survival rates, complete response (CR), event-free survival (EFS), and safety. P values for secondary endpoints and subgroups are nominal as there was no adjustment of p values for multiple analyses. Results: 302 patients were randomized to G (148) or TC (154). Preselected TCs were mainly LI (77%) predominantly HMAs (86% of the patients randomized to LI), or HI (21%), with only 6 patients (2%) in the BSC subset. Baseline variables were well balanced across the 2 treatment arms. For G vs TC respectively, age ≥65 y in 51.4% vs 40.3% with median age 65y vs 63y, ECOG PS 2 in 15.5% vs 20.8%, poor risk cytogenetics in 44.6% vs 42.2%, refractory AML in 44.6% vs 33.1%, prior HCT in 18.2% vs 26%, a majority of patients were in second or subsequent relapse after ≥ 2 prior therapies (54.7% vs 56.5%). Median number of treatment cycles was short (3 cycles for G vs 2 cycles for TC). Median follow up was 21.6 months. Most common causes of treatment discontinuation were disease progression (35.2% for G vs 38.1% for TC), or death (15.2% for G vs 18.4% for TC). Median OS on G was 6.4 months vs 5.4 months for TC and not statistically significant (OS HR 0.88, 95% CI 0.67, 1.14, log rank p value 0.3). There was no significant difference in OS between G and each of the LI and HI preselected subsets. However, several other planned prospective subgroups favored G with OS HR 95% CI upper limit ≤ 1.0 including patients &lt;65y (HR 95% CI 0.47, 0.97, p 0.032) ; ECOG PS 0-1 (HR 95% CI 0.57, 1.0, p 0.049); refractory AML (HR 95% CI 0.38, 0.89, p 0.013); lower peripheral blood (PB) disease burden of ≤ 30% PB blasts (HR 95% CI 0.46, 0.92, p 0.015); and those who received at least 4 cycles in either treatment arm (HR 95% CI 0.36, 0.95 , p 0.031). The 12- and 24-month survival rates for G vs TC respectively were 32% vs 26%; and 19% vs 10%. Median EFS was short with 3 months for G vs 2.4 months for TC; log rank p 0.005. CR rate was 12.8% for G vs 7.1% for TC (p 0.051). CR + CR with partial hematologic recovery (CRh) rate was double for G with 16.9% compared to 7.8% for TC (p 0.007). Composite CR (CRc) or CR+ CR with incomplete hematologic recovery (CRi) rate was 27% for G vs 14.3% for TC (p 0.003). Adverse events (AEs) of grade ≥3, regardless of relationship to treatment, were 89% on G vs 84% on TC. Most common Grade ≥3 AEs for G vs TC respectively were febrile neutropenia (38.6% vs 38.1%); neutropenia (32.4% vs 17%); thrombocytopenia (28.3% vs 29.9%); anemia (21.4% vs 24.5%); pneumonia (18.6% vs 20.4%); and sepsis (11.7 vs 10.9%). None of the differences were significant except for neutropenia (p 0.003). Summary/Conclusions: In this randomized study in r/r AML after intensive chemotherapy, G did not significantly improve OS compared to standard of care TC composed mainly of LI treatment with other HMAs. The data suggest that G may be better than TC in in some of the secondary endpoints (24-month survival rate, EFS, CR, CR+CRh, and CRc). Prospective subgroup analyses of OS suggest that younger (&lt;65 y), more fit patients (PS 0-1); with lower PB disease burden (PB blasts ≤ 30%), and those who could receive at least 4 cycles may benefit from G. The results of secondary endpoints and subgroup analyses should be interpreted with caution. Grade ≥3 AEs were the expected hematological and infection AEs with no significant differences between G and TC except for significantly higher incidence of neutropenia with G. Disclosures Roboz: Actinium: Consultancy; Mesoblast: Consultancy; Janssen: Research Funding; AbbVie: Consultancy; Astex: Consultancy; AstraZeneca: Consultancy; Novartis: Consultancy; Agios: Consultancy; Glaxo SmithKline: Consultancy; Blueprint Medicines: Consultancy; Janssen: Consultancy; Jasper Therapeutics: Consultancy; Amgen: Consultancy; Astellas: Consultancy; Bristol Myers Squibb: Consultancy; Celgene: Consultancy; MEI Pharma - IDMC Chair: Consultancy; Helsinn: Consultancy; Bayer: Consultancy; Daiichi Sankyo: Consultancy; Jazz: Consultancy; Otsuka: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy. Sanz: Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Other: Travel, accommodations, and expenses; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses, Speakers Bureau; Helsinn Healthcare: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses, Research Funding. Griffiths: Novartis: Honoraria; Abbvie: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Taiho Oncology: Consultancy, Honoraria; Apellis Pharmaceuticals: Research Funding; Astex Pharmaceuticals: Honoraria, Research Funding; Genentech: Research Funding; Boston Biomedical: Consultancy; Alexion Pharmaceuticals: Consultancy, Research Funding; Takeda Oncology: Consultancy, Honoraria. Yee: Forma Therapeutics: Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann La Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; TaiHo: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Paladin: Membership on an entity's Board of Directors or advisory committees; Otsuka: Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Bristol-Myers Squibb/Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onconova: Research Funding; Tolero: Research Funding; Jazz: Research Funding; MedImmune: Research Funding; Geron: Research Funding; Janssen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees. Kantarjian: Daiichi-Sankyo: Research Funding; BMS: Research Funding; Ipsen Pharmaceuticals: Honoraria; Astellas Health: Honoraria; Aptitude Health: Honoraria; KAHR Medical Ltd: Honoraria; Astra Zeneca: Honoraria; Pfizer: Honoraria, Research Funding; Ascentage: Research Funding; Amgen: Honoraria, Research Funding; Immunogen: Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Precision Biosciences: Honoraria; Jazz: Research Funding; NOVA Research: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Recher: Incyte: Honoraria; Janssen: Honoraria; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; MaatPharma: Research Funding; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Byrne: Karyopharm: Research Funding. Patkowska: Astellas Pharma, Inc.: Consultancy, Other: Travel fees; KCR US, Inc.: Consultancy; Bristol-Myers Squibb: Other: Travel fees; Jazz Pharmaceuticals: Other: Travel fees; Angelini Pharma: Honoraria, Other: Travel fees; Novartis: Honoraria, Other: Travel fees; Servier: Honoraria, Other: Travel fees; Pfizer: Other: Travel fees; AMGEN: Honoraria. Kim: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AIMS Biosciense: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AML-Hub: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BL & H: Research Funding; BMS & Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Boryung Pharm Co.: Consultancy; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Consultancy, Honoraria; LG Chem: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria; Pintherapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Honoraria, Speakers Bureau; SL VaxiGen: Consultancy, Honoraria; VigenCell: Consultancy, Honoraria. Stock: Pfizer: Consultancy, Honoraria, Research Funding; amgen: Honoraria; agios: Honoraria; jazz: Honoraria; kura: Honoraria; kite: Honoraria; morphosys: Honoraria; servier: Honoraria; syndax: Consultancy, Honoraria; Pluristeem: Consultancy, Honoraria. Illes: Janssen, Celgene, Novartis, Pfizer, Takeda, Roche: Consultancy; Takeda, Seattle Genetics: Research Funding; Novartis, Janssen, Pfizer, Roche: Other: Travel, Accommodations, Expenses. Fenaux: Abbvie: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Syros Pharmaceuticals: Honoraria. Miyazaki: Pfizer: Honoraria; Bristol-Myers Squibb: Honoraria; Abbvie: Honoraria; Novartis: Honoraria; Nippon-Shinyaku: Honoraria; Chugai: Honoraria; Janssen: Honoraria; Sumitomo-Dainippon: Honoraria, Research Funding; Astellas: Honoraria; Eisai: Honoraria; Daiichi-Sankyo: Honoraria; Takeda: Honoraria; Kyowa-Kirin: Honoraria; Sanofi: Honoraria. Yamauchi: Daiichi Sankyo: Research Funding; Astellas: Research Funding; Abbie: Research Funding; Chugai: Honoraria; Pfizer: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria; Otsuka: Research Funding; Solasia Pharma: Research Funding. Hao: Astex Pharmaceuticals, Inc.: Current Employment. Keer: Astex Pharmaceuticals, Inc.: Current Employment. Azab: Astex Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Dohner: Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Berlin-Chemie: Honoraria; Abbvie: Honoraria, Research Funding; AstraZeneca: Honoraria; Agios: Honoraria, Research Funding; Astex Pharmaceuticals: Honoraria; Amgen: Honoraria, Research Funding; Astellas: Honoraria, Research Funding; GEMoaB: Honoraria; Gilead: Honoraria; Helsinn: Honoraria; Janssen: Honoraria; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Oxford Biomedica: Honoraria; Pfizer: Research Funding; Roche: Honoraria.

Abstract Background. Over 50% of CP-CML patients will achieve a deep molecular response (DMR) at some point during treatment with Tyrosine Kinase Inhibitors (TKI), where DMR is defined as BCR-ABL1 transcript levels lower than 1/10000 (or MR4). Treatment discontinuation (TD) in CP-CML patients with stable DMR is successful in approximately half of cases, with a relapse free survival (RFS) of 48-61% at 3 years. TD is considered safe, since MMR is achieved in almost all cases when TKI re-initiation is required. As such, treatment-free remission (TFR) is now usually attempted outside of clinical trials and is part of many CML guidelines. The progression to accelerated phase/blast crisis (AP/BC) after TD was considered virtually impossible for a long time. However, recent reports document at least six cases of disease progression after TD, some of which were fatal. These observations raise concerns about the safety of TD, since now the practice can no longer be considered completely immune from the risk of disease progression, an occurrence that drastically changes the patient situation and perspective when it develops. To best counsel patients and more safely apply TD, a precise quantification of the risk of progression in this setting is needed. Study Design and Methods The TFR-PRO project monitor CML patients in long term treatment and with stable DMR, followed at 28 centers in 4 different countries (Canada, Italy, Germany, Spain). Each center is expected to enroll approximately 100 patients. The following variables were measured: time adjusted rates (TAR) of molecular relapse (loss of MR3) and of progression to AP/BC; progression free and overall survival. Primary Objective To quantify the risk of progression to AP/BP, expressed as TAR, after TKI discontinuation in CML patients who undergo a first or subsequent TKI discontinuation attempt. This value will be compared to that obtained in a similar population of patients with the same characteristics who do not discontinue TKI treatment. A flexible statistical approach will allow to attribute patients to the two groups according to their decision about TKI discontinuation and to the loss of MR3. Patients eligibility includes a history of at least 3 years of TKI treatment and at least 18 months of continuous DMR. Results The study opened on July 24 th,2020. Twelve centers are presently active with 303 eligible patients registered, for a total of 1614 person years available for analysis. Median follow up is 4.99 years (range 0.39-15.00 years), median age at diagnosis is 50.4 years and 47.9% patients are female. Sokal score (available in 147 patients) is low in 44.90%, intermediate in 32.65% and high in 22.45%. A total of 116 patients (38.28%) attempted TD at some point; 10 patients (3.30%) attempted TD twice. Loss of MR3 occurreded in 44/116 (37.93%) patients after TD for a TAR of 15.69/100 person years, (95% confidence interval (CI) [11.68-21.09]), but also in patients who did not attempt TD (21/187, or 11.23%), TAR: 1.83/100 person years, 95%CI [1.19-2.81], p&lt;0.0001. No patient progressed to AP/BC and therefore the TAR of progression is 0% with an upper value of 95%CI of 1.07/100 person years for patients who attempted TD, and with an upper value of 95%CI of 0.26/100 person years for patients who did not attempt TD. Conclusions These preliminary results obtained in a real world scenario indicate that approximately 40% of eligible patients attempt TD. The loss of MR3 after TD seem to happen less frequently (38%) than previously reported. Patients who discontinue treatment have a significantly higher risk of losingMR3 than those who continue treatment, and the risk of progression to AP/BC is lower than 1.07/100 person years. More patients need to be enrolled in this study in order to better estimate this latter number. Disclosures Assouline: Gilead: Speakers Bureau; Jewish General Hospital, Montreal, Quebec: Current Employment; Johnson&Johnson: Current equity holder in publicly-traded company; Novartis: Honoraria, Research Funding; Eli Lilly: Research Funding; Roche/Genentech: Research Funding; Takeda: Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; Amgen: Current equity holder in publicly-traded company, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Abruzzese: Pfizer: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Elena: CELGENE: Other: funding for meeting participation; PFIZER: Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Membership on an entity's Board of Directors or advisory committees; GILEAD: Membership on an entity's Board of Directors or advisory committees. Saussele: Roche: Honoraria; Pfizer: Honoraria; Incyte: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Gambacorti-Passerini: Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy.

Background. BL is a rare, high-grade B-cell lymphoma that is often studied in trials with small sample sizes. Historical definitions of "low-risk BL" vary between studies, use arbitrary cutoffs for lactate dehydrogenase (LDH), and identify a small favorable group, leaving &gt;80-90% of patients (pts) in an undifferentiated "high-risk" category. A validated prognostic index will help compare study cohorts and better define good-prognosis pts for whom reduced treatment would be appropriate vs a poor-prognosis group in need of new approaches. Herein, we constructed and validated a simplified prognostic model for BL applicable to diverse clinical settings across the world. Methods. We derived the BL-IPI from a large real-world evidence cohort of US adults treated for BL in 2009-2018 (Evens A, Blood 2020). Progression-free survival (PFS) from diagnosis until BL recurrence, progression, death, or censoring was the primary outcome. We first determined the best prognostic cutoffs for age, LDH (normalized to local upper limit normal, ULN), hemoglobin (Hgb), and albumin. Independent risk factors were ascertained by forward stepwise selection into Cox regression from candidate variables: age, sex, HIV+ status, ECOG performance status (PS) ≥2, advanced stage (3/4), involvement of &gt;1 extranodal site, bone marrow, central nervous system (CNS), values of LDH, Hgb, and albumin. Derivation models used multiple imputation to mitigate bias from missing data and reported hazard ratios (HR) with 95% confidence interval (CI). BL-IPI groups, defined by inspection of survival curves, were compared using log-rank test for trend. We validated performance of the BL-IPI in an external retrospective dataset of BL pts treated contemporaneously in centers from the United Kingdom, Scandinavia, Canada, and Australia. Results. Characteristics of pts in the derivation (N= 633) and validation (N=457) cohorts are shown in the Table. Age ≥40 years (yr), LDH &gt;3xULN, Hgb &lt;11.5 g/dL, and albumin &lt;3.5 g/dL were determined as optimal prognostic cutoffs. Age ≥40 yr, PS ≥2, stage 3/4, involvement of marrow, CNS, LDH &gt;3xULN, low Hgb, and low albumin were associated with inferior PFS in univariate tests. In the multivariable model age ≥40 yr, LDH &gt;3xULN, PS ≥2, and CNS involvement were selected as 4 independent prognostic factors; adding stage did not enhance the model. The model was simplified to 3 groups with 0 (low risk; 18% of pts), 1 (intermediate risk; 36% of pts; HR=3.14; 95%CI, 1.61-6.14), or 2-4 factors (high risk; 46% of pts; HR=6.52; 95%CI, 3.48-12.20; Fig A) with 3 yr PFS of 92%, 72%, and 53%, respectively (P&lt;.001, Fig. B); median PFS was reached only in the high-risk group (46 months, 95%CI, 19-53). BL-IPI was similarly prognostic for overall survival (OS, P&lt;.001; Fig. C). Among pts with stage III/IV (historically classified as "high-risk" and constituting 78% of all pts in the cohort), the BL-IPI further discriminated subgroups with 3 yr PFS of 87%, 71%, and 52%, respectively (P&lt;.001; Fig. D), and OS of 95%, 75%, and 57%, respectively (P&lt;.001; Fig. E). In addition, BL-IPI was prognostic regardless of HIV status, in the subcohort treated with rituximab (3 yr PFS: 92%, 73%, and 55%, respectively, P&lt;.001), and among pts treated with specific regimens: CODOX-M/IVAC±R (3 yr PFS: 88%, 67%, 61%, respectively, P=.004), DA-EPOCH-R (3 yr PFS, 87%, 73%, 51%, respectively, P&lt;.001), or hyperCVAD/MA±R (3yr PFS: 100%, 80%, 54%, respectively, P&lt;.001). In the international validation cohort, fewer pts had CNS involvement; most received CODOX-M/IVAC+R; and PFS/OS estimates at 3 yr were higher. BL-IPI categories were of similar size (low-risk 15%, intermediate-risk 35%, high-risk 50%), and provided similar risk discrimination (Harrell's C=.65 in both datasets). PFS at 3 yr was 96%, 82%, and 63%, respectively (P&lt;.001; Fig. F), and OS was 99%, 85%, and 64%, respectively (P&lt;.001; Fig. G). In the validation cohort, BL-IPI remained prognostic in the subsets receiving rituximab (P&lt;.001) and in advanced stage (P&lt;.001). Conclusions. BL-IPI is a novel prognostic index specific to BL, which was validated to allow for simplified stratification and comparison of risk distribution in geographically diverse cohorts. The index identified a low-risk group with PFS &gt;90-95%, which could be targeted with future strategies for treatment de-escalation. Conversely, only about 55-60% of pts in the high-risk group achieved cure with currently available immunochemotherapy. Disclosures Olszewski: Spectrum Pharmaceuticals: Research Funding; Genentech, Inc.: Research Funding; TG Therapeutics: Research Funding; Adaptive Biotechnologies: Research Funding. Jakobsen:Takeda: Honoraria. Collins:ADC Therapeutics: Consultancy, Honoraria; Celleron: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen: Research Funding; BeiGene: Consultancy; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding; Taekda: Consultancy, Honoraria, Other: travel, accommodations, expenses, Speakers Bureau; Roche: Consultancy, Honoraria, Other: travel, accommodations, expenses , Speakers Bureau; Pfizer: Honoraria; Celgene: Research Funding. Cwynarski:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Atara: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau. Bachanova:Incyte: Research Funding; Karyopharma: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; FATE: Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. Danilov:Abbvie: Consultancy; BeiGene: Consultancy; Nurix: Consultancy; Celgene: Consultancy; Gilead Sciences: Research Funding; Takeda Oncology: Research Funding; Pharmacyclics: Consultancy; Bayer Oncology: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy; Astra Zeneca: Consultancy, Research Funding; Verastem Oncology: Consultancy, Research Funding; Karyopharm: Consultancy; Aptose Biosciences: Research Funding; Bristol-Myers Squibb: Research Funding; Rigel Pharmaceuticals: Consultancy. Diefenbach:Trillium: Research Funding; Millenium/Takeda: Research Funding; MEI: Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; Incyte: Research Funding; LAM Therapeutics: Research Funding; Denovo: Research Funding. Epperla:Pharmacyclics: Honoraria; Verastem Oncology: Speakers Bureau. Farooq:Kite, a Gilead Company: Honoraria. Feldman:Pfizer: Research Funding; Portola: Research Funding; Janssen: Speakers Bureau; AstraZeneca: Consultancy; Cell Medica: Research Funding; Seattle Genetics, Inc.: Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau; Viracta: Research Funding; Trillium: Research Funding; Rhizen: Research Funding; Corvus: Research Funding; BMS: Consultancy, Honoraria, Research Funding; Kite: Honoraria, Other: Travel expenses, Speakers Bureau; Celgene: Honoraria, Research Funding; Takeda: Honoraria, Other: Travel expenses; Amgen: Research Funding; Pharmacyclics: Honoraria, Other, Speakers Bureau; Abbvie: Honoraria; Bayer: Consultancy, Honoraria; Eisai: Research Funding; Kyowa Kirin: Consultancy, Research Funding. Gerrie:AbbVie: Consultancy, Honoraria, Research Funding; Astrazeneca: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Roche: Research Funding; Sandoz: Consultancy. Jagadeesh:Regeneron: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Debiopharm Group: Research Funding; MEI Pharma: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees. Kamdar:BMS: Consultancy; Abbvie: Consultancy; Karyopharm: Consultancy; Celgene: Consultancy; AstraZeneca: Consultancy; Pharmacyclics: Consultancy; Seattle Genetics: Speakers Bureau. Karmali:Takeda: Research Funding; AstraZeneca: Speakers Bureau; BeiGene: Speakers Bureau; Karyopharm: Honoraria; BMS/Celgene/Juno: Honoraria, Other, Research Funding, Speakers Bureau; Gilead/Kite: Honoraria, Other, Research Funding, Speakers Bureau. Khan:Seattle Genetics: Research Funding; Janssen: Honoraria; Pharmacyclics: Honoraria; Bristol Myers Squibb: Research Funding; Celgene: Research Funding. Klein:Takeda: Membership on an entity's Board of Directors or advisory committees. Lossos:Verastem: Consultancy, Honoraria; Stanford University: Patents & Royalties; Seattle Genetics: Consultancy, Other; Janssen Biotech: Honoraria; NCI: Research Funding; Janssen Scientific: Consultancy, Other. Lunning:ADC Therapeutics: Consultancy; Legend: Consultancy; Acrotech: Consultancy; AstraZeneca: Consultancy, Honoraria; Aeratech: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Verastem: Consultancy, Honoraria; TG Therapeutics: Research Funding; Novartis: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Curis: Research Funding; Bristol Meyers Squibb: Consultancy, Honoraria, Research Funding. Martin:I-MAB: Consultancy; Celgene: Consultancy; Teneobio: Consultancy; Karyopharm: Consultancy, Research Funding; Janssen: Consultancy; Sandoz: Consultancy; Bayer: Consultancy; Beigene: Consultancy; Cellectar: Consultancy; Incyte: Consultancy; Kite: Consultancy; Morphosys: Consultancy; Regeneron: Consultancy. Martinex-Calle:Abbvie: Other: Travel grant. Naik:Celgene: Other: advisory board; Sanofi: Other: advisory board. Palmisiano:Genentech: Research Funding; AbbVie: Research Funding. Phillips:Beigene: Honoraria; Roche: Research Funding. Phillips:Seattle Genetics: Consultancy; Incyte: Consultancy, Other: travel expenses; AstraZeneca: Consultancy; Karyopharm: Consultancy; Beigene: Consultancy; Bayer: Consultancy, Research Funding; BMS: Consultancy; Pharmacyclics: Consultancy; Abbvie: Consultancy, Research Funding; Cardinal Health: Consultancy. Portell:Roche/Genentech: Consultancy, Research Funding; Infinity: Research Funding; Bayer: Consultancy; Amgen: Consultancy; TG Therapeutics: Research Funding; AbbVie: Research Funding; Pharmacyclics: Consultancy; Janssen: Consultancy; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding; Xencor: Research Funding; BeiGene: Consultancy, Research Funding. Reddy:Celgene: Consultancy; BMS: Consultancy, Research Funding; Genentech: Research Funding; Abbvie: Consultancy; KITE Pharma: Consultancy. Yazdy:Abbvie: Consultancy; Genentech: Research Funding; Octapharma: Consultancy; Bayer: Honoraria. Smith:Bristol Meyers Squibb: Research Funding; Ayala: Research Funding; Seattle Genetics: Research Funding; Portola: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; Incyte: Research Funding; Ignyta: Research Funding; Genentech: Research Funding; De Novo Biopharma: Research Funding; AstraZeneca: Consultancy; Millenium/Takeda: Consultancy; Beigene: Consultancy; Bayer: Research Funding; AstraZeneca: Research Funding; Acerta Pharma BV: Research Funding; Karyopharm: Consultancy. Cheah:Celgene, F. Hoffmann-La Roche, Abbvie, MSD: Research Funding; Celgene, F. Hoffmann-La Roche, MSD, Janssen, Gilead, Ascentage Pharma, Acerta, Loxo Oncology, TG therapeutics: Honoraria. El-Galaly:F. Hoffmann-La Roche: Current Employment, Other: Support of parent study and funding of editorial support. Evens:Research To Practice: Honoraria, Speakers Bureau; Mylteni: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria, Research Funding; MorphoSys: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria.

Abstract Background Survival rates for older pts with advanced HL (aged ≥60 yrs) were historically poor with doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD). Reasons may include decreased tolerance of therapy, increased toxicity (particularly with bleomycin), comorbidities, and disease biology. The pivotal phase 3 ECHELON-1 study demonstrated superior 2-yr modified progression-free survival (mPFS) with frontline brentuximab vedotin + doxorubicin, vinblastine and dacarbazine (A+AVD) vs ABVD in pts with stage III/IV cHL (Connors JM et al, NEJM 2018). The study allowed entry of older pts, with no upper age limit. Alternative dosing schedules of the A+AVD regimen have been studied (e.g., sequential brentuximab vedotin before and after AVD; NCT01476410, Evens AM et al, J Clin Oncol 2018). We report efficacy and safety results from ECHELON-1 for older pts with cHL and compare these with those for pts aged <60 yrs. Methods mPFS per independent review facility (IRF) for pts ≥60 years was a prespecified subgroup analysis of ECHELON-1. Additional exploratory safety and efficacy analyses were also assessed and compared with younger pts (<60 yrs). The study was not powered for age-based subgroup analyses; p-values are descriptive without multiplicity adjustment. Results 14% (186/1334) of pts in the intent-to-treat (ITT) population were aged ≥60 yrs (A+AVD, n=84; ABVD, n=102) and included in the sub analyses. Median age (range) of older pts was: A+AVD, 68.0 yrs (60-82); ABVD, 66.0 yrs (60-83). Baseline pt and disease characteristics in older pts were similar in both arms. ECOG PS scores were 0 (36% vs 36%), 1 (52% vs 54%), and 2 (12% vs 10%) in A+AVD and ABVD arms, respectively. Pts received a median of 6 cycles with mean relative dose intensities for each drug (%) in older pts of: A+AVD, 92.3, 96.6, 93.3, and 97.9; ABVD, 97.3, 88.7, 93.3, and 95.9. With median follow-up of ~25 months, 2-yr mPFS per IRF was similar in both arms for older ITT pts (A+AVD 70.3% [95% CI: 58.4, 79.4] vs ABVD 71.4% [95% CI: 60.5, 79.8]; HR=1.00 [95% CI: 0.58, 1.72]; p=0.993). An exploratory analysis of standard PFS per investigator (INV) showed HR=0.85 ([95% CI: 0.49, 1.48]; p=0.576) (Table 1). For older pts with stage IV cHL (A+AVD n=51; ABVD n=67), there was an increase in 2-yr PFS per INV with A+AVD vs ABVD (74.0% [95% CI: 59.5, 84.0] vs 59.9% [95% CI: 45.6, 71.5]; HR, 0.66 [95% CI: 0.34, 1.26]; p=0.20); mPFS per IRF improvement with A+AVD in older stage IV pts was lower (HR=0.80; [95% CI: 0.42, 1.53]). In younger stage III/IV pts (<60 yrs) 2-yr mPFS per IRF and PFS per INV were also higher compared with older pts in both arms (Table 1). 66 of 83 older A+AVD pts required ≥1 dose modification of brentuximab vedotin, reasons were: dose reduction (n=27), dose held (n=4), dose delayed (n=51), brentuximab vedotin discontinued (n=17). In older pts, grade (G) 3/4 AEs occurred in 88% of A+AVD pts vs 80% ABVD pts; for younger pts, rates were 82% (A+AVD) vs 63% (ABVD) (Table 2). In older pts there were 3 (4%) on-study deaths in the A+AVD arm (1 each: hemophagocytosis, neutropenic sepsis, and myocardial infarction) and 5 (5%) with ABVD (all pulmonary-related). In pts <60 yrs, there were 6 on-study deaths (1%) with A+AVD vs 8 (1%) with ABVD. G3 neutropenia in older pts was (70%) A+AVD pts vs (59%) ABVD pts, and febrile neutropenia (FN) in 31 (37%) vs 17 (17%) pts. In older pts who had G-CSF primary prophylaxis (PP) neutropenia was seen in 4/10 (40%) A+AVD pts vs 1/9 (11%) ABVD pts (on-study FN in 3 [30%] vs 2 [22%] pts). In older pts, treatment-emergent peripheral neuropathy (PN) was reported in 54 (65%) of A+AVD pts vs 42 (43%) of ABVD pts (G≥3 in 15 [18%] vs 3 [3%] pts), respectively. In pts <60 yrs PN was reported in 388 (67%) A+AVD pts vs 244 (43%) ABVD pts (G≥3 in 55 [9%] vs 8 [1%] pts), respectively. In older pts at last follow-up, 65% (35/54) of A+AVD pts and 60% (25/42) of ABVD pts had complete resolution (A+AVD, 39%; ABVD, 38%) or improvement (A+AVD, 26%; ABVD, 21%) of PN events. 2% older A+AVD pts had pulmonary AEs (both G1/2 pulmonary infiltration) vs 13% older ABVD pts. Conclusions For older ECHELON-1 pts, mPFS and PFS were similar in both arms. In the larger subgroup of younger pts, mPFS and PFS were improved vs older pts. As expected, incidence of treatment-emergent AEs was higher in older pts, with regimen-specific AEs seen, including fatal pulmonary events in ABVD pts. The high incidence of FN in older A+AVD pts points to the need for G-CSF PP. Disclosures Evens: Acerta: Consultancy; Pharmacyclics International DMC: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Affimed: Consultancy; Janssen: Consultancy; Abbvie: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Tesaro: Research Funding; Novartis: Consultancy. Connors:Merck: Research Funding; Amgen: Research Funding; Takeda: Research Funding; Roche Canada: Research Funding; NanoString Technologies: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies, Research Funding; Seattle Genetics: Honoraria, Research Funding; Janssen: Research Funding; F Hoffmann-La Roche: Research Funding; Bayer Healthcare: Research Funding; Cephalon: Research Funding; Bristol Myers-Squibb: Research Funding; Lilly: Research Funding; Genentech: Research Funding. Younes:Sanofi: Honoraria; Merck: Honoraria; Astra Zeneca: Research Funding; Celgene: Honoraria; Incyte: Honoraria; Seattle Genetics: Honoraria; Bayer: Honoraria; Novartis: Research Funding; Curis: Research Funding; J&J: Research Funding; Genentech: Research Funding; Takeda: Honoraria; Roche: Honoraria, Research Funding; Abbvie: Honoraria; Janssen: Honoraria, Research Funding; Pharmacyclics: Research Funding; BMS: Honoraria, Research Funding. Ansell:Merck & Co: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Celldex: Research Funding; Bristol-Myers Squibb: Research Funding. Radford:Takeda: Consultancy, Research Funding, Speakers Bureau; GlaxoSmithKline: Equity Ownership; AstraZeneca: Equity Ownership; Seattle Genetics: Consultancy, Speakers Bureau; ADC Therapeutics: Consultancy, Research Funding; Novartis: Consultancy, Speakers Bureau; Pfizer: Research Funding; Celgene: Research Funding; BMS: Consultancy, Speakers Bureau. Feldman:Seattle Genetics: Research Funding, Speakers Bureau; Janssen: Speakers Bureau; Pharmacyclics: Speakers Bureau; Johnson and Johnson: Speakers Bureau; Celgene: Speakers Bureau; Portola: Research Funding; KITE: Speakers Bureau. Tuscano:Takeda: Research Funding; Genentech: Consultancy, Research Funding; Amgen: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Research Funding. Oki:Seattle Genetics: Research Funding; Takeda Millenium: Honoraria, Research Funding; Jazz Pharmaceuticals: Employment. Grigg:Roche: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Pocock:Kent & Canterbury Hospital: Employment. Dlugosz-Danecka:Roche: Consultancy; Servier: Consultancy. Fenton:Seattle Genetics, Inc.: Employment, Equity Ownership. Engley:Seattle Genetics: Employment. Liu:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Miao:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Jolin:Takeda Pharmaceuticals International Co.: Employment. Gautam:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Gallamini:Takeda: Consultancy, Speakers Bureau.

Abstract Background: A new subcutaneous formulation of rituximab (RSC) has been developed which offers reduced treatment burden for patients compared to intravenous rituximab (RIV) as well as resource savings at the treatment facility. Additionally, availability of RSC would potentially allow patients to be treated primarily IV-free with orally administered partner therapies. The Phase 3 SABRINA study (NCT01200758) investigated induction RIV or RSC plus chemotherapy followed by maintenance RIV or RSC in patients with follicular lymphoma (FL). Pharmacokinetic non-inferiority was previously reported for RSC (1400mg) compared with RIV (375mg/m2) as well as comparable efficacy and safety (Davies et al. Lancet Oncol 2014;15:343-52; Davies, et al. Haematologica 2015;100:P687). Here we present updated efficacy and safety results including overall response rates (ORR) at the end of maintenance and time to event (progression-free [PFS], overall [OS], and event-free [EFS] survival) data with a median follow-up of 37 months. Methods: Patients with treatment-naïve CD20+ grade 1-3a FL (n=410) were randomized to receive RIV or RSC, stratified by FL International Prognostic Index score, chemotherapy regimen, and region. All patients received RIV 375mg/m2 in Cycle 1; for Cycles 2-8, patients received RIV 375mg/m2 or RSC 1400mg every 3 weeks. Patients received ≤8 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or 8 cycles of CVP (cyclophosphamide, vincristine and prednisone). During maintenance, patients received RIV or RSC every 8 weeks for 2 years. Non-serious adverse events (AEs) were reported for 28 days following the last dose of rituximab. Serious AEs (SAEs) were recorded for 1 year post-treatment or until the start of new anti-lymphoma treatment. SAEs considered possibly related to study treatment were recorded indefinitely. Results: Based on investigator assessments for the intent-to-treat population (RIV n=205; RSC n=205), ORR at the end of maintenance was comparable between treatment arms: (78.1%, 95% CI [71.3, 83.9] for RIV vs. 77.9%, 95% CI [71.0, 83.9] for RSC) (Table 1). Analyses of the time-to-event endpoints PFS (HR, 0.84, 95% CI [0.57, 1.23]) (Fig.1), EFS (HR, 0.91, 95% CI [0.64, 1.31), and OS (HR, 0.81, 95% CI [0.42, 1.57) showed no differences in efficacy for the SC vs. the IV formulation. In total, 407 patients received ≥1 dose of rituximab (safety population). Six RSC patients discontinued treatment after Cycle 1 (RIV in both arms) and were included in the RIV safety population (RIV n=210; RSC n=197); 86% of patients started maintenance (RIV n=178, 85%; RSC n=172, 87%). Overall, there were similar incidences of patients with ≥1 AE (95% vs. 96%), grade ≥3 AEs (55% and 56%), and SAEs (34% and 37%) for RIV vs. RSC, respectively (Table 2). The most frequent AEs reported overall (RIV vs. RSC) were neutropenia (27% vs. 32%), nausea (22% vs. 31%), constipation (26% vs. 25%), cough (13% vs. 23%), and fatigue (18% vs. 20%). The most frequently reported AEs during the maintenance phase of the study were upper respiratory tract infection (7% vs. 11%) and cough (11% vs. 12%) for RIV vs. RSC, respectively. Overall, AEs associated with B-cell depletion, including neutropenia, febrile neutropenia, and grade ≥3 infections, were balanced between the SC and IV treatment arms. The change in route of administration led to an expected higher incidence of local cutaneous reactions in the RSC arm (2% RIV vs. 23% RSC) with injection site erythema, injection site pain, and rash being most frequently reported. All reported events, except for 1 AE of injection site rash in the RSC arm at Cycle 2, were of mild or moderate intensity (grade ≤2). Incidence of local cutaneous reactions decreased over subsequent treatment cycles. At data cut-off, 36 deaths had been reported: 20 (9.8%) in the RIV arm and 16 (7.8%) in the RSC arm. Conclusions: Overall, there were no new clinically relevant safety signals observed with RSC and the safety profile was comparable to that of RIV. Response rates as well as PFS and OS data for rituximab SC were comparable to rituximab IV and indicate that the anti-lymphoma activity of rituximab is not impaired when given subcutaneously. The availability of RSC administration over approximately 6 minutes has positive implications for patient and healthcare professional convenience, as well as healthcare resource savings, without compromising efficacy or safety. Figure 1. Figure 1. Disclosures Davies: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Honoraria; Janssen: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel to scientific conferences, Research Funding; GSK: Research Funding; Karyopharma: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodation, expenses, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Bayer: Research Funding; Pfizer: Research Funding. Leppä:Roche: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Takeda Pharmaceuticals: Consultancy, Honoraria, Other: Travel expenses; Janssen: Consultancy, Research Funding; Mundipharma: Research Funding; CTI Bio Pharma: Consultancy; Bayer: Other: Travel expenses, Research Funding. Cotting:Roche: Employment, Equity Ownership. Veenstra:Roche: Employment. Zharkov:Roche: Employment. Dixon:Roche Products Limited: Employment, Equity Ownership. Barrett:Roche Products Ltd.: Employment, Equity Ownership. Macdonald:Roche: Consultancy, Honoraria; Lundbeck Canada: Consultancy, Honoraria; Gilead: Consultancy, Honoraria.

Abstract Abstract 3829 Poster Board III-765 Introduction A large proportion of patients (pts) with myelodysplastic syndromes (MDS) become dependent on red blood cell (RBC) transfusions, escalating the risk of transfusional hemosiderosis and associated adverse effects. The US03 study was designed to evaluate the long-term efficacy and safety of the oral iron chelator, deferasirox, administered once-daily in pts with lower-risk MDS. 173 pts at 45 centers in the US and Canada enrolled in the 1-year core phase of the study and 83 pts participated in the 2-year extension phase. We now present data from pts who have completed 2 years of deferasirox treatment. Methods US03/E is an ongoing, Phase II, open-label, 3-year trial in pts with Low- or Int-1 IPSS-risk MDS. Eligible pts had transfusional iron overload (serum ferritin ≥1000 μg/L and >20 units of RBC transfusions) with serum creatinine (SCr) ≤2-fold the upper limit of normal (ULN). Initial deferasirox dose was 20 mg/kg/day, which could be increased up to 40 mg/kg/day based on tolerability and response criteria. Serum ferritin and creatinine were monitored monthly. Baseline features 83 pts entered the extension study; mean age was 68 years (range 21–90) with 41 men and 42 women. IPSS risk groups were Low in 23 (28%) pts and Int-1 in 60 (72%). Mean serum ferritin level at the beginning of the extension phase was 2496 μg/L (range 546–7770); mean lifetime number of transfusions was 83.6 (range 20–364) and the mean duration of transfusion therapy was 4.6 (2–12) years. 18 (22%) pts were receiving growth factors (8 darbepoetin, 5 G-CSF, 4 epoetin alpha and 1 tranexamic acid), and 13 pts were receiving other MDS specific therapies (5 decitabine, 4 azacitidine, 3 lenalidomide, and 1 hydroxyurea). The calculated creatinine clearance at extension study entry was normal (>80 mL/min) in 20 (25%) pts and abnormal in 59 (75%), including mild renal insufficiency (51–80 mL/min) in 41 (52%) pts, moderate (30–50 mL/min) in 16 (20%) and severe in 2 (3%). Two-year efficacy results At the time of this analysis, 54 pts completed 2 years of treatment (1 year in the core and one year in the extension portion of the study). Over 24 months, the mean dose of deferasirox was 22.8 mg/kg/day and the mean transfusion rate was 4 units/month. Serum ferritin results are available from 50 pts who have received deferasirox for 100 weeks (Figure). The mean serum ferritin level decreased significantly from study baseline: 3002 to 2069 μg/L at 100 weeks (Δ=933 μg/L; P<0.001, signed rank test). Six (7%) pts experienced hematological improvement according to IWG 2000 criteria. Three patients experienced an erythroid response (major, n=2; minor n=1); only one who achieved a minor response received MDS treatment with darbepoetin. Others included major platelet response (n=1; not receiving MDS treatment), major neutrophil response (n=1; not receiving MDS treatment) and one combined major platelet and neutrophil response while receiving G-CSF and decitabine treatment. Safety Of 83 pts, 35 (42%) discontinued from the study: 8 (9.6%) due to abnormal laboratory values (increase of creatinine 6, thrombocytopenia 1, and neutropenia and thrombocytopenia 1), 8 (9.6%) due to adverse events (gastrointestinal symptoms 3, Clostridium dificile infection 1, renal dysfunction 1, cardiac symptoms 1, unknown 1), 11 (13.2%) due to serious AEs with an outcome of death (none of the deaths were related to deferasirox) and 8 (9.6%) due to MDS progression/AML. Of 67 pts with normal baseline SCr, 24 (30%) had an increase in SCr values above the ULN on at least two occasions (3.0 mg/dL max SCr). Of 16 pts with abnormal baseline SCr, one had an increase to above the ULN on at least two occasions. New onset of grades 3 and 4 thrombocytopenia and neutropenia occurred in 15 (18%) and 29 (35%) pts, respectively. Conclusions In pts with lower-risk MDS and iron overload, deferasirox significantly reduced serum ferritin over 2 years. Deferasirox was generally well tolerated over 2 years. The final year of this study will continue to assess the long-term safety and efficacy of deferasirox in these lower-risk MDS pts with iron overload. Disclosures: Raza: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Esposito:Novartis Pharmaceuticals: Employment. Martinez-Lopez:Novartis Pharmaceuticals: Employment. Paley:Novartis Pharmaceuticals: Employment, Equity Ownership. Besa:Novartis: Research Funding, Speakers Bureau.

Abstract Background: Current treatments for Waldenström's macroglobulinemia (WM) are not curative, and a standard of care does not exist. MYD88 L265P, a mutation identified in patients (pts) with WM, signals through interleukin-1 receptor-associated kinase 1 and Bruton's tyrosine kinase (BTK), leading to the constitutive activation of the NF-κB pathway (Yang, 2013). Ibrutinib (ibr), an oral inhibitor of BTK, attenuates the interaction between MYD88 and BTK and blocks BTK-dependent downstream signaling, inducing apoptosis of WM cells (Treon, 2012). In a phase 2 trial of ibr in previously treated WM, durable responses were seen (overall response rate [ORR] of 90.5% and an estimated 24-month PFS of 69.1%; Treon, 2015) leading to FDA and EU approval of ibr in pts with WM. Single-agent ibr indicated favorable responses in pts with WM failing prior monoclonal antibody therapy (Treon, 2015). Here, we report on the efficacy and safety of single-agent ibr in pts with WM refractory to the last rituximab-containing therapy. Methods: Pts with centrally confirmed diagnosis of WM and symptomatic disease requiring treatment per 2nd International Workshop on WM criteria were enrolled in this open-label, international, multicenter, phase 3 substudy (PCYC-1127 Arm C). Other key inclusion criteria included disease refractory to the last rituximab-containing therapy defined as either relapse after <12 months or failure to achieve at least a minor response. Pts received oral ibr 420 mg daily continuously until progressive disease (PD) or unacceptable toxicity. Main objectives include progression-free survival, ORR, improvement of hemoglobin, and overall survival. Results: Among the 31 pts treated, the median age was 67 years (range, 47-90); 19% had an ECOG performance status of 2, and 42% had a high International Prognostic Score System for WM (IPSSWM). The median number of prior therapies was 4 (range, 1-8; 68% with ≥3 prior therapies). In addition to rituximab, the most common prior treatments included corticosteroids and alkylating agents (Table). The initial ORR at a median follow-up of 7.7 months was 84%, with a major response rate (≥PR) of 65%. Five pts required plasmapheresis, with no additional need beyond Cycle 1 in 4 pts. Baseline median hemoglobin of 10.3 g/dL increased to 11.4 g/dL after one cycle and baseline median IgM of 3830 mg/dL declined by >50% by end of Cycle 1 (Figure), with continued improvement over time. Any-grade adverse events (AEs) occurred in 29 pts (94%), and grade ≥3 AEs in 16 pts (52%). Most common any-grade AEs (>15%) included diarrhea (39%); hypertension (23%); neutropenia and upper respiratory tract infections (URTIs; 19% each); pyrexia; thrombocytopenia; and increased tendency to bruise (16% each). Common grade ≥3 AEs included neutropenia (13%); anemia, diarrhea, hypertension, and thrombocytopenia (6% each). Overall, 16 pts (52%) developed infections (10% grade ≥3). Serious AEs occurred in 6 pts (19%). All patients remain alive at data cut, with no events of IgM flare, atrial fibrillation or major bleeding. Dose reductions occurred in 4 pts (13%), with no dose reductions for hematologic toxicity. Two pts discontinued ibr-1 pt due to early PD (MYD88 wild-type), and 1 pt discontinued after 8 days of treatment due to an AE of gastrointestinal AL amyloidosis. Overall, 29 pts (94%) continue on ibr therapy. Additional data will be provided. Conclusions: Single-agent ibr is highly active in this heavily pretreated rituximab-refractory WM population, with a high ORR. No new or unexpected AEs were observed, with a manageable safety profile consistent with previous studies of single-agent ibr. Table 1. Baseline characteristics N=31 Median age, years (range) Age ≥ 65 years, n (%) 67 (47-90) 17 (55) ECOG, n (%) 0-1 2 25 (81) 6 (19) IPSSWM, n (%) Low Intermediate High 7 (23) 11 (35) 13 (42) Median serum IgM, mg/dL (range) 3830 (740-10700) Median b2-microglobulin, mg/L (range) 3.6 (1.7-24) Median hemoglobin levels, g/dL (range) 10.3 (6.4-14.6) Median platelet count (109/L) (range) 218 (51-896) Median absolute neutrophil count (109/L) (range) 2.9 (0.7-15.4) Median number of prior therapies (range) 4 (1-8) Types of prior therapies, n (%) Rituximab Corticosteroids Alkylating agentVinca alkaloids Proteasome inhibitor Purine analog Anthracyclines Immunomodulating agent Nucleoside analog Other 31 (100) 25 (81) 25 (81) 14 (45) 14 (45) 13 (42) 8 (26) 2 (6) 2 (6) 4 (13) Prior autologous stem cell transplantation, n (%) 2 (6) Figure 1. Figure 1. Disclosures Dimopoulos: Genesis Pharma: Research Funding; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Onyx: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Trotman:Janssen: Research Funding. Macdonald:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; Lundbeck Canada: Consultancy, Honoraria, Other: Travel Expenses; Roche: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding. Tam:Janssen: Consultancy, Honoraria, Research Funding. Tournilhac:Roche: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Mundipharma: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Celgene: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Janssen: Honoraria; GSK: Other: Travel Expenses, Research Funding; Amgen: Other: Travel Expenses, Research Funding. Ma:Abbvie: Research Funding; Xeme: Research Funding; Novartis: Research Funding; Idera: Consultancy, Honoraria; Genentech: Consultancy, Honoraria, Speakers Bureau; Giliead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Research Funding. Heffner:Amgen: Consultancy. Shustik:Amgen: Honoraria; Roche: Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy; Novartis: Consultancy. García-Sanz:Janssen: Honoraria, Other: Travel, Accommodations, Expenses; Takeda: Honoraria, Other: Travel, Accommodations, Expenses; Novartis: Research Funding. Fernández de Larrea:Celgene: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses. Castillo:Otsuka: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; Biogen IDEC: Consultancy; Millennium: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding. Kyrtsonis:Amgen: Research Funding; Lilly: Research Funding; Genesis: Honoraria; Millenium: Research Funding. Leblond:Janssen: Consultancy, Honoraria, Speakers Bureau; Mundipharma: Honoraria; Roche: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau. Symeonidis:Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; Celgene: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; Roche: Consultancy, Other: Travel, Accommodations, Expenses; Amgen: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; Pfizer: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; MSD: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; Takeda: Research Funding; Actellion: Research Funding; Proton-Pharma: Research Funding; Astellas: Other: Travel, Accommodations, Expenses, Research Funding; Teva: Other: Travel, Accommodations, Expenses, Research Funding; ApoPharma: Research Funding; Genzyme: Other: Travel, Accommodations, Expenses, Research Funding; Alexion: Other: Travel, Accommodations, Expenses, Research Funding; GenesisPharma: Consultancy; Glaxo: Consultancy. Singh:Pharmacyclics LLC, an AbbVie Company: Employment. Li:Pharmacyclics LLC, an AbbVie Company: Employment. Graef:AbbVie: Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Employment, Membership on an entity's Board of Directors or advisory committees. Bilotti:Pharmacyclics LLC, an AbbVie Company: Employment. Treon:Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; Onyx: Consultancy, Research Funding. Buske:Roche: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Celgene: Honoraria, Other: Travel, Accommodations, Expenses; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: Consultancy.

INTRODUCTION Upper limb prostheses are commonly prescribed for people with upper limb absence (ULA) to restore function, cosmesis, and assist with activities of daily living. However, nearly one in five people with ULA chooses not to use a prosthesis1 and instead turns to alternative technology and adaptations, pointing to factors beyond prostheses that shape perceptions of ability and quality of life. We examined through interviews the lived experiences of people with ULA framed around their perceptions of ability, device use, and quality of life. Abstract PDF Link: https://jps.library.utoronto.ca/index.php/cpoj/article/view/32001/24423 How to cite: McDonald C.L, Bennett C.L, Rosner D.K, Steele K.M. I AM THE BOY WITH ONE HAND WHO CAN DO ANYTHING”: PERCEPTIONS OF ABILITY AMONG PEOPLE WITH UPPER LIMB ABSENCE. CANADIAN PROSTHETICS & ORTHOTICS JOURNAL, VOLUME 1, ISSUE 2, 2018; ABSTRACT, POSTER PRESENTATION AT THE AOPA’S 101ST NATIONAL ASSEMBLY, SEPT. 26-29, VANCOUVER, CANADA, 2018. DOI: https://doi.org/10.33137/cpoj.v1i2.32001 Abstracts were Peer-reviewed by the American Orthotic Prosthetic Association (AOPA) 101st National Assembly Scientific Committee. http://www.aopanet.org/

It was thirty years ago this past March that Alberta’s Select Special Committee on Upper HouseReform released its influential 1985 report that helped to reframe discussions on Senate reformand popularize proposals for a “Triple-E” Senate. The Committee’s report built on the work ofa Canada West Foundation task force that argued eff ective regional representation in Parliament requires a Senate that is equal (in terms of provincial representation), elected, and effective (in terms of its legislative powers). The Alberta Committee’s Report popularized these ideas and helped to frame the Senate reform debate in terms of commitments to electoral democracy and rebalancing federalism, especially in terms of the representation of territorial interests at the federal level.

This study identifies the current spatial and temporal patterns of threats to at-risk freshwater fishes within Canada. Data for 65 at-risk freshwater fishes were collated from the Committee on the Status of Endangered Wildlife in Canada Assessment and Status reports with threat calculators. Using these data, the overall threat impact level and the threat impact of the 11 categories in the threat calculator were compared for all species and separately by conservation status, which indicates their risk of extinction. These threats were also compared temporally to a study completed in 2006 and spatially between National Freshwater Biogeographic Zones. The threats of invasive species and pollution had the highest impacts, accounting for 18.9% and 16.8% of the weighted impact on at-risk freshwater fishes, respectively. Since 2006, all threats have been increasing, except for natural disasters. The Great Lakes–Upper St. Lawrence River Biogeographic Zone had significantly more at-risk freshwater fishes and overall weighted threat impact than other zones, with pollution, invasive species, and natural system modification contributing the most to the imperilment in this region.

INTRODUCTION Spinal cord injury (SCI) remains a leading cause of long-term disability in the United States with the majority of injuries resulting in incomplete quadriplegia due to cervical lesions.1 This leads to significant neurological impairment including upper extremity (UE) weakness and decreased independence with self-care activities of daily living (ADLs). Previous work demonstrated that using a myoelectric elbow-wrist-hand orthosis as a therapeutic adjunct to a multi-week rehabilitation regimen resulted in decreased UE motor impairment and increased function in stroke survivors with moderate UE hemiparesis.2 The purpose of this case study was to determine if wearing a myoelectric elbow-wrist-hand orthosis reduces upper extremity motor impairment and increases functional ability in an individual with chronic, incomplete spinal cord injury and resultant quadriplegia. Abstract PDF Link: https://jps.library.utoronto.ca/index.php/cpoj/article/view/32021/24439 How to cite: Wengerd L. FUNCTIONAL UTILITY OF WEARING A MYOELECTRIC ORTHOSIS FOR UPPER EXTREMITY PARALYSIS DUE TO SPINAL CORD INJURY. CANADIAN PROSTHETICS & ORTHOTICS JOURNAL, VOLUME 1, ISSUE 2, 2018; ABSTRACT, POSTER PRESENTATION AT THE AOPA’S 101ST NATIONAL ASSEMBLY, SEPT. 26-29, VANCOUVER, CANADA, 2018. DOI: https://doi.org/10.33137/cpoj.v1i2.32021 Abstracts were Peer-reviewed by the American Orthotic Prosthetic Association (AOPA) 101st National Assembly Scientific Committee. http://www.aopanet.org/

INTRODUCTION Upper limb prosthetic acceptance seems to be relatively unchanged from 1958 where it was measured to be 75% for transradial, 61% for transhumeral, and 35% for shoulder disarticulation levels. A practitioner survey from 2013 by the author found this to be largely unchanged at 79.6%, 57.8%, and 32.8% respectively. An upper limb meta-analysis showed that the most significant factors affecting prosthetic rejection using a median rating were function, comfort, ease of use, weight, heat, lack of sensory feedback, inconvenience, lifestyle, dissatisfaction with technology, irritation, and availability of services. An earlier survey by the author condensed these factors of rejection to amputation level, functional advantage, and comfort, and included confidence of the prosthetist, availability of therapy, and support of the patient context. Also it was speculated that the value of factors influencing rejection of prostheses may not be simply the converse of those accepting the prosthesis but different scales. Abstract PDF Link: https://jps.library.utoronto.ca/index.php/cpoj/article/view/32045/24459 How to cite: Stark G E. FACTOR ANALYSIS OF UPPER LIMB PROSTHETIC ACCEPTANCE FROM RETROSPECTIVE PROSTHETIC CLINICIAN SURVEY. CANADIAN PROSTHETICS & ORTHOTICS JOURNAL, VOLUME 1, ISSUE 2, 2018; ABSTRACT, ORAL PRESENTATION AT THE AOPA’S 101ST NATIONAL ASSEMBLY, SEPT. 26-29, VANCOUVER, CANADA, 2018. DOI: https://doi.org/10.33137/cpoj.v1i2.32045 Abstracts were Peer-reviewed by the American Orthotic Prosthetic Association (AOPA) 101st National Assembly Scientific Committee. http://www.aopanet.org/

INTRODUCTION Winging scapula is a rare condition that can be painful and debilitating to the upper extremity involved1. This condition can affect the functional ability of the upper extremity, resulting in loss of range of motion, decreased power, and pain.1 The purpose of this study was to introduce and determine the clinical applicability of a custom thermoplastic scapulothoracic orthosis to aid in management of winging scapula. The thermoplastic scapulothoracic orthosis offers total contact and provides anterior-posterior compressive forces to stabilize the winging scapula. This design provides a semi-rigid structure that is lightweight and allows user adjustability. The study highlights the potential applicability of the custom thermoplastic scapulothoracic orthosis in the categories of pain, active range of motion at the shoulder, and overall self-reported activities of daily living. Abstract PDF Link: https://jps.library.utoronto.ca/index.php/cpoj/article/view/32043/24457 How to cite: Brown S, Trexler G. CASE STUDY: THERMOPLASTIC SCAPULOTHORACIC ORTHOSIS FOR TREATMENT OF WINGING SCAPULA. CANADIAN PROSTHETICS & ORTHOTICS JOURNAL, VOLUME 1, ISSUE 2, 2018; ABSTRACT, ORAL PRESENTATION AT THE AOPA’S 101ST NATIONAL ASSEMBLY, SEPT. 26-29, VANCOUVER, CANADA, 2018. DOI: https://doi.org/10.33137/cpoj.v1i2.32043 Abstracts were Peer-reviewed by the American Orthotic Prosthetic Association (AOPA) 101st National Assembly Scientific Committee. http://www.aopanet.org/

INTRODUCTION This case series presents prescription, evaluation, fitting and initial functional benefits of a myoelectric elbow- wrist-hand orthosis with active grasp. Custom fit, myoelectric orthoses are now also being provided to patients with upper extremity paresis due conditions such as stroke, brachial plexus injury, spinal cord injury, multiple sclerosis and amyotrophic lateral sclerosis to enable them to self-initiate and control movement of a partially paretic limb using their own volitional myoelectric signals. A recent study of 18 chronic stroke participants demonstrated functional improvements on the Fugl-Meyer Impairment Scale (FM) and a battery of functional tasks with this device.1 Abstract PDF Link:https://jps.library.utoronto.ca/index.php/cpoj/article/view/32022/24440 How to cite: Shoemaker E. MYOELECTRIC ELBOW-WRIST-HAND ORTHOSIS WITH ACTIVE GRASP FOR PATIENTS WITH STROKE: A CASE SERIES. CANADIAN PROSTHETICS & ORTHOTICS JOURNAL, VOLUME 1, ISSUE 2, 2018; ABSTRACT, ORAL PRESENTATION AT THE AOPA’S 101ST NATIONAL ASSEMBLY, SEPT. 26-29, VANCOUVER, CANADA, 2018. DOI: https://doi.org/10.33137/cpoj.v1i2.32022 Abstracts were Peer-reviewed by the American Orthotic Prosthetic Association (AOPA) 101st National Assembly Scientific Committee. http://www.aopanet.org/

INTRODUCTION Myoelectric hands progressed from single grip hands (traditional myoelectric devices (TH)) to be multi-grip hands (MGH) which are hypothesized to bring more degrees of freedom, greater range of motion and improved grasping capabilities1,2. Their impact on patients’ lives has been documented in only a few case studies. The Strategic Consortium for Upper Limb Prosthetic Technologies (SCULPT) aims to assess the potential benefits MGH with respect to function and patient satisfaction compared to TH systems. Abstract PDF Link: https://jps.library.utoronto.ca/index.php/cpoj/article/view/32049/24463 How to cite: Popovic I, Cutti A, Ryan T, Schaefer M, Andres E, Wuestefeld D, Winkler C, Baun K, Bischof B, Braatz F, Miguelez J, Conyers D, Hahn A. DO MULTI-GRIP HANDS INCREASE FUNCTION AND PATIENT SATISFACTION WHEN COMPARED TO TRADITIONAL MYOELECTRIC HANDS? CANADIAN PROSTHETICS & ORTHOTICS JOURNAL, VOLUME 1, ISSUE 2, 2018; ABSTRACT, POSTER PRESENTATION AT THE AOPA’S 101ST NATIONAL ASSEMBLY, SEPT. 26-29, VANCOUVER, CANADA, 2018. DOI: https://doi.org/10.33137/cpoj.v1i2.32049 Abstracts were Peer-reviewed by the American Orthotic Prosthetic Association (AOPA) 101st National Assembly Scientific Committee. http://www.aopanet.org/

INTRODUCTION Additive Manufacturing (AM), colloquial known as 3D-printing, has been deemed capable to revolutionize a great number of industries, including the Health Care industry.1 In the field of upper limb prosthetics, it has been attempted to leverage the potential advantages of AM, such as crowd based design optimization, infrastructure independent fabrication, and economical material use, in the interest of providing low-cost, readily available devices to recipients whose needs were only insufficiently met by traditional approaches of device prescription and fitting. While the popular media has been quick to emphasize the potential – perceived or real – of 3D printed prostheses, clinicians have generally been less euphoric and the base of scientific evidence on questions related to these applications has been small.2 As with most research endeavors in prosthetics and orthotics, recruiting sufficient sample sizes to allow solid conclusions is a perennial challenge also in this sub-field. As a consequence, the effectiveness of the many 3D-printed upper limb devices made by volunteers of the E-nable community (Fig.1) is yet to be determined. Self-reported outcome assessment tools can somewhat mitigate the issue of low sample sizes. However, none have been applied to a wider range of device classes, to allow comparative analyses across those. We describe the development and preliminary testing of an online based survey tool to generate comparison outcome data for a wide variety of upper limb prosthetics devices, including varieties that are 3D-printed by hobbyists. Abstract PDF Link: https://jps.library.utoronto.ca/index.php/cpoj/article/view/32009/24428 How to cite: Mankoff J, Savage S, Eckert S, Ngo C, Fiedler G. USER EXPERIENCES WITH TRADITIONAL AND 3D-PRINTED UPPER EXTREMITY PROSTHESES, DEVELOPMENT OF A COMPREHENSIVE SURVEY INSTRUMENT. CANADIAN PROSTHETICS & ORTHOTICS JOURNAL, VOLUME 1, ISSUE 2, 2018; ABSTRACT, POSTER PRESENTATION AT THE AOPA’S 101ST NATIONAL ASSEMBLY, SEPT. 26-29, VANCOUVER, CANADA, 2018. DOI: https://doi.org/10.33137/cpoj.v1i2.32009 Abstracts were Peer-reviewed by the American Orthotic Prosthetic Association (AOPA) 101st National Assembly Scientific Committee. http://www.aopanet.org/

INTRODUCTION 3D printing for non‐weight‐bearing upper extremity prostheses is becoming increasingly popular as a method of fabrication.1 Some clinics in North America have begun using 3D printing to fabricate lower extremity diagnostic sockets (Figure 1). The strength requirements for upper extremity prostheses are not as rigorous as the strength requirements for lower extremity prostheses. Therefore, strength testing on 3D-printed lower extremity sockets is one of the first steps that needs to be conducted to ensure patient safety. 3D-printed prosthetic sockets are becoming an alternative option to traditional methods because it is possible to customize different parameters to create a strong structure. Infill percentage is an important parameter to research as this can have an influence on the strength of 3D printed sockets.2 As both prosthetists and healthcare professionals, there is a need to become more involved in the process of designing and testing 3D printed sockets. The purpose of this study is to test how changing the infill percentage affects the ultimate strength of a 3D printed transtibial socket during initial contact. Abstract PDF Link: https://jps.library.utoronto.ca/index.php/cpoj/article/view/32038/24453 How to cite: Campbell L, Lau A, Pousett B, Janzen E, Raschke S.U. HOW INFILL PERCENTAGE AFFECTS THE ULTIMATE STRENGTH OF A 3D-PRINTED TRANSTIBIAL SOCKET. CANADIAN PROSTHETICS & ORTHOTICS JOURNAL, VOLUME 1, ISSUE 2, 2018; ABSTRACT, POSTER PRESENTATION AT THE AOPA’S 101ST NATIONAL ASSEMBLY, SEPT. 26-29, VANCOUVER, CANADA, 2018. DOI: https://doi.org/10.33137/cpoj.v1i2.32038 Abstracts were Peer-reviewed by the American Orthotic Prosthetic Association (AOPA) 101st National Assembly Scientific Committee. http://www.aopanet.org/

The Elder Abuse Awareness Committee of Chatham Kent, Ontario employed ten seniors (65 years of age or older) from this rural community to conduct an investigation of the knowledge and prevalence of elder abuse among their peers. The 236 study participants interviewed by the specifically trained elders were predominantly female ranging in age from 55 to over 90. The majority were still living in their own homes, had completed high school or post-secondary education, and reported relatively good health. These attributes predicted a rate of disclosed elder abuse within the lower end of the four to ten percent range typically reported in the literature. However, an incidence rate of 19.1% was reported nearly double the upper end of the range, with 137 separate acts of verbal, emotional, and financial abuse reported by participants to their peers. Formal paid caregivers were identified as the most frequent perpetrators though two thirds of the incidents were not reported to anyone at the time they occurred primarily due to embarrassment, fear, being dependent upon the abuser, or simply not knowing who to tell about the abuse. In the minority of instances when the abuse was reported the most common sources informed were the police, a family physician, or a helping professional in the community. KEYWORDS: Elder abuse, rural, Canada

INTRODUCTION Brachial plexus injuries are often caused by trauma, tumors or inflammation. The severity of the injury may vary, however in most traumatic cases, the supraclavicular region is impacted. Depending on the severity of the injury, surgery is often indicated early due to the likelihood of nerve regeneration. Surgical procedures include neurolysis, nerve grafting and neurotisation; where approximately 45% will regain adequate function to perform activities of daily living (ADLs) and return to work. According to current data, approximately 9,700 individuals per year will remain disabled due to the injury. For individuals where surgical intervention has not provided improvement in function, alternative solutions must be investigated. Particularly for those with bilateral involvement, potential solutions include orthotic technology. Like users of prosthetic technology, there is a wide array of technology available, intended to meet the diverse needs experienced by the population of individual who have lost function of the upper limbs. This paper describes the challenges experienced by an individual with bilateral brachial plexus injuries and addresses the case solutions using collaborative inter-professional practice.1-4 Abstract PDF Link: https://jps.library.utoronto.ca/index.php/cpoj/article/view/32047/24461 How to cite: Delgado C, Latour D. USE OF EXTERNALLY-POWERED ORTHOSIS TO ADDRESS COMPLEXITIES ASSOCIATED WITH BILATERAL BRACHIAL PLEXOPATHY. CANADIAN PROSTHETICS & ORTHOTICS JOURNAL, VOLUME 1, ISSUE 2, 2018; ABSTRACT, ORAL PRESENTATION AT THE AOPA’S 101ST NATIONAL ASSEMBLY, SEPT. 26-29, VANCOUVER, CANADA, 2018. DOI: https://doi.org/10.33137/cpoj.v1i2.32047 Abstracts were Peer-reviewed by the American Orthotic Prosthetic Association (AOPA) 101st National Assembly Scientific Committee. http://www.aopanet.org/

ObjectiveAs a basis for an application in anatomy education, vision‐based spatial abilities tests have been correlated with drawings of objects from haptic perception. Decreasing haptic perception while increasing working memory has been found to decrease performance on drawings of objects from haptic perception. The objective of the current study was to correlate spatial abilities to the effect of working memory on drawings of objects from haptic perception.MethodsA cohort of 24 medical graduates was enrolled in a prospective study. Ethics committee approval and written informed concent were obtained. Spatial abilities were measured with a redrawn Vandenberg and Kuse Mental Rotations Tests in two (MRTA) and three (MRTC) dimensions and a Surface Development Test (SDT). Experiment was done within a one‐month rotation preparing for residency. Eighteen objects constructed from 10 cubes glued together, similar to Shepard and Metzler's objects, were drawn by participants from haptic perception. Drawings were scored by one judge. Time performance was defined as the time to perform all drawings/number of correct drawing. The first and second exercise were done before and within a one‐week drawing course, respectively. In the first exercise, object could be touched by participants for up to seven minutes while drawing the object. In the second exercise, 30 seconds were allowed for haptic perception of the object, 15 seconds to memorize, and up to 375 seconds to draw the object without any further haptic access to the object. The maximum score was 24 for each of MRTA and MRTC, 60 for SDT, 18 for the drawing score, and 420 seconds for time performance. Descriptive statistics included median and lower and upper quartiles. Spearman's correlation coefficient (and associated p‐value) was used to correlate the change in drawing score and time performance to MRTA, MRTC and SDT scores.ResultsCorrelations of change in drawing score between the first and second exercice [5 (4, 8.5)] with MRTA [10.5 (7.5, 14)], MRTC [8.0 (5, 10.5)] and SDT [44 (36, 46.5)] scores were − 0.371 (p = 0.0747), −0.454 (p = 0.0257) and −0.556 (p = 0.0048), respectively. Similarly, correlations of change in time performance between the first and second exercice [106 (27, 321) seconds] with MRTA, MRTC and SDT scores were −0.288 (p = 0.1716), −0.426 (p < 0.0378) and −0.439 (p = 0.0318), respectively.ConclusionSpatial abilities tests were correlated to the effect of working memory on drawings of objects from haptic perception. These findings imply a possible neural pathway between spatial abilities in the parietal lobe and working memory in the central executive lateral prefrontal cortex of brain.Support or Funding InformationThis study was supported by an internal grant from the Department of Surgery, Université de Sherbrooke, Sherbrooke, QC, Canada.

ObjectiveAs a basis for an application in anatomy education, vision‐based spatial abilities tests have been correlated with pictures of objects recognized from haptic perception. The objective of the current study was to determine the effect of short term memory on the recognition of pictures of objects from haptic perception. The hypothesis is that the use of short term memory has a negative effect on the performance.MethodsA cohort of 48 medical graduates was enrolled in a prospective study. Ethics committee approval and written informed concent were obtained. Spatial abilities were measured with a redrawn Vandenberg and Kuse Mental Rotations Tests in two (MRTA) and three (MRTC) dimensions and a Surface Development Test (SDT). In a one‐month rotation preparing for residency, the experiment was done within a one‐week drawing course before a one‐week applied anatomy course. Twenty‐five objects constructed from various shaped parts glued together were identified on a picture by participants after haptic perception. In the first exercise, participants could touch the object for up to two minutes while identifying the corresponding picture. In the second exercise, 30 seconds were allowed for haptic perception of the object, 15 seconds to memorize, and up to 75 seconds to identify the corresponding picture without any further haptic access to the object. The maximum score was 24 for each of MRTA and MRTC, 60 for SDT, and 25 for the picture score. Descriptive statistics included median and lower and upper quartiles. Spearman's correlation coefficient was used to correlate the picture score to MRTA, MRTC and SDT scores. Wilcoxon signed‐rank test was used to compare the picture score in the first and second exercise.ResultsThe picture score in the first exercise [18 (12, 21)] was correlated with MRTA [14 (9, 17)], MRTC [9.5 (6.5, 12)] and SDT [44.5 (36, 53)] scores with a correlation of 0.427 (p = 0.0025), 0.539 (p < 0.0001) and 0.429 (p = 0.0024), respectively. Similarly, the picture score in the second exercise [10 (7, 13)] was correlated with MRTA, MRTC, and SDT scores with a correlation of 0.444 (p = 0.0014), 0.384 (p = 0.0064) and 0.323 (p = 0.0236), respectively. The picture score in the first and second exercise was different (p < 0.0001).ConclusionHaptics is involved in the handling of anatomical structures. Vision‐based spatial abilities tests were correlated with pictures of objects recognized from haptic perception. The use of short term memory was found to have a negative effect on the performance. These findings on haptic perception and short term memory have promising avenues for education in the anatomy laboratory.Support or Funding InformationThis study was supported by an internal grant from the Department of Surgery, Université de Sherbrooke, Sherbrooke, QC, Canada.

Abstract Objectives To determine the effect of therapeutic anticoagulation, with low molecular weight heparin (LMWH) or unfractionated heparin (UFH, high dose nomogram), compared to standard care in hospitalized patients admitted for COVID-19 with an elevated D-dimer on the composite outcome of intensive care unit (ICU) admission, non-invasive positive pressure ventilation, invasive mechanical ventilation or death up to 28 days. Trial design Open-label, parallel, 1:1, phase 3, 2-arm randomized controlled trial Participants The study population includes hospitalized adults admitted for COVID-19 prior to the development of critical illness. Excluded individuals are those where the bleeding risk or risk of transfusion would generally be considered unacceptable, those already therapeutically anticoagulated and those who have already have any component of the primary composite outcome. Participants are recruited from hospital sites in Brazil, Canada, Ireland, Saudi Arabia, United Arab Emirates, and the United States of America. The inclusion criteria are: Laboratory confirmed COVID-19 (diagnosis of SARS-CoV-2 via reverse transcriptase polymerase chain reaction as per the World Health Organization protocol or by nucleic acid based isothermal amplification) prior to hospital admission OR within first 5 days (i.e. 120 hours) after hospital admission; Admitted to hospital for COVID-19; One D-dimer value above the upper limit of normal (ULN) (within 5 days (i.e. 120 hours) of hospital admission) AND EITHER: D-Dimer ≥2 times ULN OR D-Dimer above ULN and Oxygen saturation ≤ 93% on room air; > 18 years of age; Informed consent from the patient (or legally authorized substitute decision maker). The exclusion criteria are: pregnancy; hemoglobin <80 g/L in the last 72 hours; platelet count <50 x 109/L in the last 72 hours; known fibrinogen <1.5 g/L (if testing deemed clinically indicated by the treating physician prior to the initiation of anticoagulation); known INR >1.8 (if testing deemed clinically indicated by the treating physician prior to the initiation of anticoagulation); patient already prescribed intermediate dosing of LMWH that cannot be changed (determination of what constitutes an intermediate dose is to be at the discretion of the treating clinician taking the local institutional thromboprophylaxis protocol for high risk patients into consideration); patient already prescribed therapeutic anticoagulation at the time of screening [low or high dose nomogram UFH, LMWH, warfarin, direct oral anticoagulant (any dose of dabigatran, apixaban, rivaroxaban, edoxaban)]; patient prescribed dual antiplatelet therapy, when one of the agents cannot be stopped safely; known bleeding within the last 30 days requiring emergency room presentation or hospitalization; known history of a bleeding disorder of an inherited or active acquired bleeding disorder; known history of heparin-induced thrombocytopenia; known allergy to UFH or LMWH; admitted to the intensive care unit at the time of screening; treated with non-invasive positive pressure ventilation or invasive mechanical ventilation at the time of screening; Imminent death according to the judgement of the most responsible physician; enrollment in another clinical trial of antithrombotic therapy involving hospitalized patients. Intervention and comparator Intervention: Therapeutic dose of LMWH (dalteparin, enoxaparin, tinzaparin) or high dose nomogram of UFH. The choice of LMWH versus UFH will be at the clinician’s discretion and dependent on local institutional supply. Comparator: Standard care [thromboprophylactic doses of LMWH (dalteparin, enoxaparin, tinzaparin, fondaparinux)] or UFH. Administration of LMWH, UFH or fondaparinux at thromboprophylactic doses for acutely ill hospitalized medical patients, in the absence of contraindication, is generally considered standard care. Main outcomes The primary composite outcome of ICU admission, non-invasive positive pressure ventilation, invasive mechanical ventilation or death at 28 days. Secondary outcomes include (evaluated up to day 28): All-cause death Composite of ICU admission or all-cause death Composite of mechanical ventilation or all-cause death Major bleeding as defined by the ISTH Scientific and Standardization Committee (ISTH-SSC) recommendation; Red blood cell transfusion (>1 unit); Transfusion of platelets, frozen plasma, prothrombin complex concentrate, cryoprecipitate and/or fibrinogen concentrate; Renal replacement therapy; Hospital-free days alive; ICU-free days alive; Ventilator-free days alive; Organ support-free days alive; Venous thromboembolism (defined as symptomatic or incidental, suspected or confirmed via diagnostic imaging and/or electrocardiogram where appropriate); Arterial thromboembolism (defined as suspected or confirmed via diagnostic imaging and/or electrocardiogram where appropriate); Heparin induced thrombocytopenia; Trajectories of COVID-19 disease-related coagulation and inflammatory biomarkers. Randomisation Randomisation will be stratified by site and age (>65 versus ≤65 years) using a 1:1 computer-generated random allocation sequence with variable block sizes. Randomization will occur within the first 5 days (i.e. 120 hours) of participant hospital admission. However, it is recommended that randomization occurs as early as possible after hospital admission. Central randomization using an interactive web response system will ensure allocation concealment. Blinding (masking) No blinding involved. This is an open-label trial. Numbers to be randomised (sample size) 462 patients (231 per group) are needed to detect a 15% risk difference, from 50% in the control group to 35% in the experimental group, with power of 90% at a two-sided alpha of 0.05. Trial Status Protocol Version Number 1.4. Recruitment began on May 11th, 2020. Recruitment is expected to be completed March 2022. Recruitment is ongoing. Trial registration ClinicalTrials.gov Identifier: NCT04362085 Date of Trial Registration: April 24, 2020 Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Becker, Bonny. The Sniffles for Bear. Cambridge, Mass.: Candlewick Press, 2011. Print Any book featuring the shenanigans of curmudgeonly Bear and winsome Mouse is met with enthusiasm in my house. Bear has a terrible cold and he responds to his condition with his usual verbose intolerance. Again, it is utterly creative and unstoppably committed Mouse - every introvert’s secret fantasy friend - to the rescue. While the dialogue is as snappy and satisfying as ever, it is Denton’s illustrations, their clean, clear detail and spot-on visual characterization that put these excellent books over the top. Has there ever been a cold suffered more intensely than Bear’s? The physical language and facial expressions on the cover alone speak to the depths Bear’s lethargy and irritation and Mouse’s unquenchable joie de vivre. Becker’s willingness to use evocative, mildly esoteric words, rather than baffling children, engages them with exotic cadence and apt expressions of the characters’ compelling idiosyncrasies. The mood and temperament of the books is unfailingly cozy and pastoral. (Is it Upper Canada or New England pastoral, though? I can’t decide.) One always worries that the return of appealing characters in new stories will dilute their charms but that has, luckily, not been the case with Becker and Denton’s collaboration; the dynamic between Bear and Mouse continues to be clever and delightful. The exploration of friendships between the sort of oppositional temperaments that Bear and Mouse embody is a familiar theme in children’s literature. While only time will tell, there is potential that Bear and Mouse are developing as enduring a partnership as Arnold Lobel’s Frog and Toad. One keenly hopes for many more little domestic adventures to come. Highly Recommended: 4 out of 4 starsReviewer: Matilda Roche Matilda spends her days lavishing attention on the University of Alberta’s metadata but children’s illustrated books, literature for young adults and graphic novels also make her heart sing. Her reviews benefit from the critical influence of a four year old daughter and a one year old son – both geniuses. Matilda’s super power is the ability to read comic books aloud.

When we think of United Nations (UN) peacekeepers, the first image that is conjured in our mind is of an individual sporting a blue helmet or a blue beret (fig. 1). While simple and uncomplicated, these blue accessories represent an expression and an embodiment resembling that of a warrior, sent to bring peace to conflict-torn communities. UN peacekeeping first conceptually emerged in 1948 in the wake of the Arab-Israeli war that ensued following the United Kingdom’s relinquishing of its mandate over Palestine, and the proclamation of the State of Israel. “Forged in the crucible of practical diplomacy” (Rubinstein 16), unarmed military observers were deployed to Palestine to monitor the hostilities and mediate armistice agreements between Israel and its Arab neighbours. This operation, the United Nations Truce Supervision Organization (UNTSO), significantly exemplified the diplomatic and observational capabilities of military men, in line with the UN Charter’s objectives of international peace and security, setting henceforth a basic archetype for international peacekeeping. It was only in 1956, however, that peacekeeping formally emerged when armed UN forces deployed to Egypt to supervise the withdrawal of forces occupying the Suez Canal (informally known as the ‘Second Arab-Israeli’ war). Here, the formation of UN peacekeeping represented an international pacifying mechanism comprised of multiple third-party intermediaries whereby peaceful resolution would be achieved by transcending realist instincts of violence for political attainment in favour of applying a less-destructive liberal model of persuasion, compromise, and perseverance (Howard). ‘Blue helmet’ peacekeeping operations continue to be regarded by the UN as an integral subsidiary instrument of its organisation. At present, there are 12 active peacekeeping operations led by the UN Department of Peacekeeping across the world (United Nations Peacekeeping). Fig. 1: United Nations Mission in South Sudan (UNMISS) sporting blue berets (https://www.gov.uk/government/news/uk-troops-awarded-un-medals-for-south-sudan-peacekeeping-mission) But where did the blue helmets and berets originate from? Rubinstein details a surprisingly mundane account of the origins of the political accessory that is now a widely recognised symbol for UN peacekeepers’ uniforms. Peacekeepers’ uniforms initially emerged from the ad hoc need to distinguish UN troops from those of the armed forces in a distinctive dress during the 1947 UNTSO mission by any means and material readily available, such as armbands and helmets (Henry). The era of early peacekeeping operations also saw ‘observers’ carry UN flags and paint their vehicle white with ‘UN’ written in large black letters in order to distinguish themselves. The blue helmets specifically came to be adorned during the first peacekeeping operation in 1956 during the Suez crisis. At this time, Canada supplied a large number of non-combatant troops whose uniform was the same as the belligerent British forces, party to the conflict. An effort to thus distinguish the peacekeepers was made by spray-painting surplus World War II American plastic helmet-liners, which were available in quantity in Europe, blue (Urquhart; Rubenstein). The two official colours of the UN are ‘light blue’ and ‘white’. The unique light “UN” blue colour, in particular, was approved as the background for the UN flag in the 1947 General Assembly Resolution 167(II), alongside a white emblem depicting a map of the world surrounded by two olive branches. While the UN’s use of the colour was chosen as a “practical effect of identifying the Organization in areas of trouble and conflict, to any and all parties concerned”, the colour blue was also specifically chosen at this time as “an integral part of the visual identity of the organisation” representing “peace in opposition to red, for war” (United Nations). Blue is seen to be placed in antithesis to the colour red across several fields including popular culture, and even within politics, as a way to typically indicate conflict between two warring groups. Within popular culture, for example, many films in the science fiction, fantasy, or horror genres, use a clearly demarcated, dichotomous ‘red vs. blue’ colour scheme in their posters (fig. 2). This is also commonly seen in political campaign posters, for example during the 2021 US presidential election (fig. 3). Fig. 2: Blue and red colour schemes in film posters (left to right: Star Wars: The Force Awakens (2015), Captain Marvel (2019), and The Dead Don’t Die (2019)) Fig. 3: Biden (Democratic party) vs. Trump (Republican party) US presidential election (https://www.abc.net.au/news/2020-10-15/us-election-political-parties-explained-democrats-vs-republicans/12708296) This dichotomy can be traced back to the high Middle Ages between the fourteenth and seventeenth century where the colour blue became a colour associated with “moral implications”, rivalling both the colours black and red which were extremely popular in clothing during the eras of the late Middle Ages and early Renaissance (Pastoureau 85). This ‘moral metamorphosis’ in European society was largely influenced by the views of Christian Protestant reformers concerning the social, religious, and artistic use of the colour blue (Pastoureau). A shift in the use of blue and its symbolic connotations may also be seen, for example, in early Christian art and iconography, specifically those deriving from depictions of the Virgin Mary; according to Pastoureau (50), this provides the “clearest illustration of the social, religious, and artistic consequences of blue's new status”. Up until the eighteenth century, the colour blue, specifically ‘sky blue’ or light blue tones resemblant of the “UN” shade of blue, had minimal symbolic or aesthetic value, particularly in European culture and certainly amongst nobility and the upper levels of society. Historically, light blue was typically associated with peasants’ clothing. This was due to the fact that peasants would often dye their clothes using the pigment of the woad herb; however, the woad would poorly penetrate cloth fibres and inevitably fade under the effects of sunlight and soap, thereby resulting in a ‘bland’ colour (Pastoureau). Although the blue hues worn by the nobility and wealthy were typically denser and more solid, a “new fashion” for light blue tones gradually took hold at the courts of the wealthy and the bourgeoisie, inevitably becoming deeply anchored in Western European counties (Pastoureau). Here, the reorganisation of the colour hierarchy and reformulation of blue certainly resembles Pastoureau’s (10) assertion that “any history of colour is, above all, a social history”. Within the humanities, colour represents a social phenomenon and construction. Colour thus provides insights into the ways society assigns meaning to it, “constructs its codes and values, establishes its uses, and determines whether it is acceptable or not” (Pastoureau, 10). In this way, although colour is a naturally occurring phenomenon, it is also a complex cultural construct. That the UN and its subsidiary bodies, including the Department of Peacekeeping, deliberately assigned light blue as its official organisational colour therefore usefully illustrates a significant social process of meaning-making and cultural sociology. The historical transition of light blue’s association from one of poverty in and around the eighteenth century to one of wealth in the nineteenth century may perhaps also be indicative of the next transitional era for light blue in the twentieth and twenty-first centuries, representative of the amalgamation or unity between the two classes. Representing the ambitions not only of the organisation, but rather of the 193 member-states, of attaining worldwide peace, light blue may be seen as a colour of peace, as well as one of the people, for the people. This may be traced back, according to Pastoureau, as early as the Middle Ages where the colour blue was seen a colour of ‘peace’. Colours, however, do not solely determine social and cultural relevance in a given historical event. Rather, fabrics and clothing too offer “the richest and most diverse source of artifacts” in understanding history and culture. Artifacts such as UN peacekeepers’ blue berets and helmets necessarily incorporate economic, social, ideological, aesthetic, and symbolic aspects of both colour and material into the one complete uniform (Pastoureau). While the ‘UN blue’ is associated with peace, the beret, on the other hand, has been described as “an ally in the battlefield” (Kliest). The history of the beret is largely rooted in the armed forces – institutions typically associated with conflict and violence – and it continues to be a vital aspect of military uniforms worn by personnel from countries all around the globe. Given that the large majority of UN peacekeeping forces are made up of military personnel, peacekeeping, as both an action and an institution, thus adds a layer of complexity when discussing artifact symbolism. Here, a peacekeeper’s uniform uniquely represents the embodiment of an amalgamation of two traditionally juxtaposing concepts: peace, nurture, and diplomacy (often associated with ‘feminine’ qualities) versus conflict, strength, and discipline (often associated with ‘masculine’ qualities). A peacekeeper’s uniform thus represents the UN’s institutionalisation of “soldiers for peace” (Howard) who are, as former UN Secretary-General Dag Hammarskjold proclaimed, “the front line of a moral force” (BBC cited in Howard). Aside from its association with the armed forces, the beret has also been used as a fashion symbol by political revolutionaries, such as members of the ‘Black Panther Party’ (BPP) founded in the 1960s during the US Civil Rights Movement, as well as Che Guevara, prominent Leftist figure in the Cuban Revolution (see fig. 4). For, Rosabelle Forzy, CEO of beret and headwear fashion manufacturing company ‘Laulhère’, the beret is “emblematic of non-conformism … worn by people who create, commit, militate, and resist” (Kliest). Fig. 4: Berets worn by political revolutionaries (Left to right: Black Panthers Party (BPP) protesting outside of a New York courthouse (https://www.dailymail.co.uk/news/article-2988897/Black-Panther-double-cop-killer-sues-freedom-plays-FLUTE-Murderer-demands-parole-changed-fury-victim-s-widow.html), and portrait of Che Guevara) In a way, the UN’s ‘blue beret’ too bears a ‘non-conformist’ visage as its peacekeepers neither fit categorisations as ‘revolutionaries’ nor as traditional ‘soldiers’. Peacekeepers personify a cultural phenomenon that operates in a complex environment (Rubinstein). While peacekeepers retain their national military (usually camouflage) uniforms during missions, the UN headwear is a symbol of non-conformity in response to sociological preconceptions regarding military culture. In the case of peacekeeping, the implementation and longevity of peacekeepers’ uniforms has occurred through a process of what Rubinstein (50) refers to as ‘cultural’ or ‘symbolic inversion’ wherein traditional notions of military rituals and symbolism have been appropriated or ‘inverted’ and given a new meaning by the UN. In other words, the UN promotes the image of soldiers acting without the use of force in service of peace in order to encode an image of a “world transformed” through the contribution of peacekeeping toward the “elaboration of an image of an international community acting in a neutral, consensual manner” (Rubinstein, 50). Cultural inversion therefore creates a socio-political space wherein normative representations are reconfigured and conditioned as acceptable. Rubinstein argues, however, that the UN’s need to integrate individuals with such diverse backgrounds and perceptions into a collective peacekeeper identity can be problematic. Rubinstein (72) adds that the blue beret is the “most obvious evidence” of an ordinary symbol investing ‘legitimacy’ in peacekeeping through ritual repetition which still holds its cultural relevance to the present day. Arguably, institutional uniforms are symbols which profoundly shape human experience, validating contextual action according to the symbol’s meanings relevant to those wearing it. In this way, uniform symbolism not only allows us to make sense of our daily experiences, but allows us to construct and understand our identities and our interactions with others who are also part of the symbolic culture we are situated in. Consider, for example, a police officer. A police officer’s uniform not only grants them membership to the policing institution but also necessarily grants them certain powers, privileges, and jurisdictions within society which thereby impact on the way they see the world and interact with it. Necessarily, the social and cultural identity one acquires from wearing a specific uniform only effectively functions by “investing differences”, however large or small, into these symbols that “distinguish us from others” (Rubinstein, 74). For example, a policeman’s badge is a signifier that they are, in fact, part of an exclusive group that the majority of the citizenry are not. To this extent, the use of uniforms is not without its controversies or without the capacity to be misused as a tool of discrimination in a ‘them’ versus ‘us’ scenario. Referring to case regarding the beret, for example, in 2000 then US Army Chief of Staff, General Eric Shineski, announced that the black beret – traditionally worn exclusively by specialised US Army units such as ‘Rangers’ – would become a standardised part of the US Army uniform for all soldiers and would denote a “symbol of unity”. General Shineski’s decision for the new headgear symbolised “the half-million-strong army’s transition to a lighter, more agile force that can respond more rapidly to distant trouble spots” (Borger). This was, however, met with angry backlash particularly from the Rangers who stated that they “were being robbed of a badge of pride” as “the beret is a symbol of excellence … that is not to be worn by everybody” (Borger). Responses to the proposition pointed to the problem of ‘low morale’ that the military faced, which could not be fixed just by “changing hats” (Borger). In this case, the beret was identified and isolated as a tool for coordinating perceptions (Rubinstein, 78). Here, the use of uniforms is as much about being external identifiers and designating a group from another as it is about sustaining a group by means of perpetuating what Rubinstein conceptualises as ‘self-legitimation’. This occurs in order to ensure the survival of a group and is similarly seen as occurring within UN peacekeeping (Joseph & Alex). Within peacekeeping the blue beret is an effective symbol used to perpetuate self-legitimacy across various levels of the UN which construct systems, or a ‘community’, of reinforcement largely rooted on organisational models of virtue and diplomacy. In the broadest sense, the UN promotes “a unique responsibility to set a global standard” in service to creating a unified and pacific world order (Guterres). As an integral instrument of international action, peacekeeping is, by extension, necessarily conditioned and supported by this cultural model whereby the actions of individual peacekeepers are strategically linked to the symbolic capital at the broadest levels of the organisation to manage the organisation’s power and legitimacy. The image of the peacekeeper, however, is fraught with problems and, as such, UN peacekeepers’ uniforms represent discrepancies and contradictions in the UN’s mission and organisational culture, particularly with relation to the UN’s symbolic construction of community and cooperation amongst peacekeepers. Given that peacekeeping troops are made up of individuals from different ethnic, cultural, and professional backgrounds, conditions for cultural interaction become challenging, if not problematic, and may necessarily lead to cross-cultural misunderstandings, miscommunication, and conflict. This applies to the context of peacekeeper deployment to host nations amongst local communities with whom they are also culturally unfamiliar (Rubinstein, "Intervention"). According to Rubinstein ("Intervention", 528), such operations may “create the conditions under which criminal activities or the institution of neo-colonial relationships can emerge”. Moncrief adds to this by also suggesting that a breakdown in conduct and discipline during missions may also contribute to peacekeepers engaging in violence during missions. Consequently, multiple cases of misdemeanour by UN peacekeepers have been reported across the years including peacekeeper involvement in bribery, weapons trading, and gold smuggling (Escobales). One of the most notorious acts of misconduct and violence that continues to be reported in the present day, however, is of peacekeepers perpetrating sexual exploitation and abuse against host women and children. Between 2004 and 2016, for example, “the UN received almost 2,000 allegations of sexual exploitation and abuse” (Essa). According to former chief of operations at the UN’s Emergency Co-ordination Centre, Andrew Macleod, this figure may be, however, much more disturbing, estimating in general that approximately “60,000 rapes had been carried out by UN staff in the past decade” (Zeffman). An article in the Guardian reported that a 12-year-old girl had been hiding in a bathroom during a house search in a Muslim enclave of the capital, Bangui [in the Central African Republic] … . A man allegedly wearing the blue helmet and vest of the UN peacekeeping forces took her outside and raped her behind a truck. (Smith & Lewis) In the article, the assailant’s uniform (“the blue helmet and vest”) is not only described as literal imagery to contextualise the grave crime that was committed against the child. In evoking the image of the blue helmet and vest, the author highlights the uniform as a symbolic tool of power which was misused to perpetuate harm against the vulnerable civilian ‘other’. In this scenario, like many others, rather than representing peace and hope, the blue helmet (or beret) instead illustrates the contradictions of the UN peacekeeper’s uniform. Here, the uniform has consequently come to be associated as a symbol of violence, fear, and most significantly, betrayal, for the victim(s) of the abuse, as well as for much of the victim’s community. This discrepancy was also highlighted in a speech presented by former Ambassador of the UK Mission to the UN, Matthew Rycroft, who stated that “when a girl looks up to a blue helmet, she should do so not in fear, but in hope”. For many peacekeepers perpetrating sexual exploitation and abuse, particularly transactional sex, however, they “do not see themselves as abusing women”. This is largely to do with the power and privileges peacekeepers are afforded, such as ‘immunity’ – that is, a peacekeeper is granted immunity from trial or prosecution for criminal misconduct by the host nation’s judicial system. Over the years, scholarly research regarding peacekeepers’ immunity has highlighted a plethora of organisational problems within the UN, including lack of perpetrator accountability, and internal investigation or follow-up. More so, it has undoubtedly “contributed to a culture of individuals committing sexual violence knowing that they will get away with it” (Freedman). When a peacekeeper wears their uniform, they are thus imbued with the power and charged with the responsibility to properly embody and represent the values of the UN; “if [peacekeepers] don’t understand how powerful a position they are in, they will never understand what they do is actually wrong” (Elks). As such, unlike other traditional institutional uniforms, such as that of a soldier or a police officer, a peacekeeper’s uniform stands out as an enigma. One the one hand, peacekeepers channel the peaceful and passive organisational values of the UN by wearing the blue beret or helmet, whilst at the same time, they continue to sport the national military body uniform of their home country. Questions pertaining to the peacekeeper’s uniform arise and require further exploration: how can peacekeepers disassociate from their disciplined military personas and learnt combat skills if they continue to wear military camouflage during peacekeeping missions? Is the addition of the blue beret or helmet enough to reconfigure the body of the peacekeeper from one of violence, masculinity, and offence to that of peace, nurture, and diplomacy? Certainly, a range of factors are pertinent to an understanding of peacekeepers’ behaviour and group culture. But whether these two opposing identities can cohesively create or reconstitute a third identity using the positive skills and attributes of both juxtaposing institutions remains elusive. Nonetheless, the blue beret is a symbol of international hope, not only for vulnerable populations, but also for the world population collectively, as it represents neutral third-party member states working together to rebuild the world through non-combative means. References Borger, Julian. “Elite Forces Fear the Coming of the Egalitarian Beret.” The Guardian 19 Oct. 2000. <https://www.theguardian.com/world/2000/oct/19/julianborger>. Elks, Sonia. “Haitians Say Underaged Girls Were Abused by U.N. Peacekeepers.” Reuters 19 Dec. 2019. <https://www.reuters.com/article/us-haiti-women-peacekeepers-idUSKBN1YM27W>. Escobales, Roxanne. “UN Peacekeepers 'Traded Gold and Guns with Congolese rebels'.” The Guardian 28 Apr. 2008. <https://www.theguardian.com/world/2008/apr/28/congo.unitednations>. Essa, Azad. “Why Do Some Peacekeepers Rape? The Full Report.” Al Jazeera 10 Aug. 2017. <https://www.aljazeera.com/features/2017/8/10/why-do-some-peacekeepers-rape-the-full-report>. 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